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1
Laing, R. B. S., R. P. Brettle, and C. L. S. Leen. "Clinical predictors of azole resistance, outcome and survival from oesophageal candidiasis in AIDS patients." International Journal of STD & AIDS 9, no. 1 (January 1, 1998): 16–20. http://dx.doi.org/10.1258/0956462981920973.
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Summary: A retrospective review of AIDS-related oesophageal candidiasis was undertaken to identify clinical features helpful in predicting response to azole therapy and patient survival. Patients who had received daily azole prophylaxis against candidiasis were significantly less likely to respond to azole therapy than < those who had not ( P 0.001). Patients who had lost the 2 months before oesophageal candidiasis were less likely to respond to azoles < than the others ( P 0.001). Amongst those who had not received daily azoles, < + patients with a CD4 cell count 25/mm were less likely to respond to azole treatment ( P = 0.05). The median survival beyond oesophageal candidiasis was 18 months. Survival from oesophageal candidiasis was significantly poorer for patients who did not respond to azole therapy but AIDS survival did not differ between azole responders and non-responders. Non-responders who had been taking daily azole prophylaxis had the poorest survival (median = 4 months). > 5% of their body weight in 3
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Serfling, Albrecht, Johannes Wohlrab, and Holger B. Deising. "Treatment of a Clinically Relevant Plant-Pathogenic Fungus with an Agricultural Azole Causes Cross-Resistance to Medical Azoles and Potentiates Caspofungin Efficacy." Antimicrobial Agents and Chemotherapy 51, no. 10 (July 9, 2007): 3672–76. http://dx.doi.org/10.1128/aac.00654-07.
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ABSTRACT Azoles are extensively applied in agriculture and medicine, and a relationship between the development of azole resistance in agriculture and the development of azole resistance in clinical practice may exist. The maize pathogen Colletotrichum graminicola, causing cutaneous mycosis and keratitis, has been used to investigate the acquisition of resistance to an agricultural azole and the resulting cross-resistance to various medical antifungal agents. Azole-adapted strains were less sensitive to all azoles tested but showed increased sensitivity to caspofungin, amphotericin B, and nystatin. Viability staining and infection assays with excised human skin confirmed these data.
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van Ingen, Jakko, Henrich A. L. van der Lee, Antonius J. M. M. Rijs, Eveline Snelders, Willem J. G. Melchers, and Paul E. Verweij. "High-Level Pan-Azole-Resistant Aspergillosis: TABLE 1." Journal of Clinical Microbiology 53, no. 7 (April 22, 2015): 2343–45. http://dx.doi.org/10.1128/jcm.00502-15.
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High-level pan-azole-resistantAspergillus fumigatuswas recovered from four patients with chronic lung disease. In one patient, the development of progressive resistance followed long-term azole therapy and switching between antifungal azoles. The high-level pan-azole-resistant phenotypes were not associated with a specificcyp51Agene mutation. New strategies that avoid the development of progressive azole resistance are needed.
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Gonzalez-Jimenez, Irene, Jose Lucio, Alejandra Roldan, Laura Alcazar-Fuoli, and Emilia Mellado. "Are Point Mutations in HMG-CoA Reductases (Hmg1 and Hmg2) a Step towards Azole Resistance in Aspergillus fumigatus?" Molecules 26, no. 19 (October 1, 2021): 5975. http://dx.doi.org/10.3390/molecules26195975.
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Invasive aspergillosis, mainly caused by Aspergillus fumigatus, can lead to severe clinical outcomes in immunocompromised individuals. Antifungal treatment, based on the use of azoles, is crucial to increase survival rates. However, the recent emergence of azole-resistant A. fumigatus isolates is affecting the efficacy of the clinical therapy and lowering the success rate of azole strategies against aspergillosis. Azole resistance mechanisms described to date are mainly associated with mutations in the azole target gene cyp51A that entail structural changes in Cyp51A or overexpression of the gene. However, strains lacking cyp51A modifications but resistant to clinical azoles have recently been detected. Some genes have been proposed as new players in azole resistance. In this study, the gene hmg1, recently related to azole resistance, and its paralogue hmg2 were studied in a collection of fifteen azole-resistant strains without cyp51A modifications. Both genes encode HMG-CoA reductases and are involved in the ergosterol biosynthesis. Several mutations located in the sterol sensing domain (SSD) of Hmg1 (D242Y, G307D/S, P309L, K319Q, Y368H, F390L and I412T) and Hmg2 (I235S, V303A, I312S, I360F and V397C) were detected. The role of these mutations in conferring azole resistance is discussed in this work.
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Sanglard, Dominique, and Alix T. Coste. "Activity of Isavuconazole and Other Azoles against Candida Clinical Isolates and Yeast Model Systems with Known Azole Resistance Mechanisms." Antimicrobial Agents and Chemotherapy 60, no. 1 (October 19, 2015): 229–38. http://dx.doi.org/10.1128/aac.02157-15.
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ABSTRACTIsavuconazole is a novel, broad-spectrum, antifungal azole. In order to evaluate its interactions with known azole resistance mechanisms, isavuconazole susceptibility among different yeast models and clinical isolates expressing characterized azole resistance mechanisms was tested and compared to those of fluconazole, itraconazole, posaconazole, and voriconazole.Saccharomyces cerevisiaeexpressing theCandida albicansandC. glabrataATP binding cassette (ABC) transporters (CDR1,CDR2, andCgCDR1), major facilitator (MDR1), and lanosterol 14-α-sterol-demethylase (ERG11) alleles with mutations were used. In addition, pairs ofC. albicansandC. glabratastrains from matched clinical isolates with known azole resistance mechanisms were investigated. The expression of ABC transporters increased all azole MICs, suggesting that all azoles tested were substrates of ABC transporters. The expression ofMDR1did not increase posaconazole, itraconazole, and isavuconazole MICs. Relative increases of azole MICs (from 4- to 32-fold) were observed for fluconazole, voriconazole, and isavuconazole when at least two mutations were present in the sameERG11allele. Upon MIC testing of azoles with clinicalC. albicansandC. glabrataisolates with known resistance mechanisms, the MIC90s ofC. albicansfor fluconazole, voriconazole, itraconazole, posaconazole, and isavuconazole were 128, 2, 1, 0.5, and 2 μg/ml, respectively, while inC. glabratathey were 128, 2, 4, 4, and 16 μg/ml, respectively. In conclusion, the effects of azole resistance mechanisms on isavuconazole did not differ significantly from those of other azoles. Resistance mechanisms in yeasts involving ABC transporters andERG11decreased the activity of isavuconazole, whileMDR1had limited effect.
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Liepa, AJ, AJ Liepa, TC Morton, and TC Morton. "Synthesis of 1-(α-Acyloxy-2-hydroxybenzyl)Azoles and Related Compounds by an Acyl Transfer Reaction." Australian Journal of Chemistry 42, no. 11 (1989): 1961. http://dx.doi.org/10.1071/ch9891961.
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Novel azole adducts were produced by reaction of azoles and 2-acyloxyaryl aldehydes. The mechanism of the reaction involves attack by the azole at the carbonyl group and transfer of the acyl group to form an azole-substituted benzylic ester. 2-Acyloxyaryl ketones did not undergo an analogous reaction. An aminal was formed rather than an azole-substituted benzylic carbonate when a 2-aryl aldehyde carbonate was used as substrate.
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Gonzalez-Jimenez, Irene, Jose Lucio, Jorge Amich, Isabel Cuesta, Rafael Sanchez Arroyo, Laura Alcazar-Fuoli, and Emilia Mellado. "A Cyp51B Mutation Contributes to Azole Resistance in Aspergillus fumigatus." Journal of Fungi 6, no. 4 (November 26, 2020): 315. http://dx.doi.org/10.3390/jof6040315.
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The emergence and spread of Aspergillus fumigatus azole resistance has been acknowledged worldwide. The main problem of azole resistance is the limited therapeutic options for patients suffering aspergillosis. Azole resistance mechanisms have been mostly linked to the enzyme Cyp51A, a target of azole drugs, with a wide variety of modifications responsible for the different resistance mechanisms described to date. However, there are increasing reports of A. fumigatus strains showing azole resistance without Cyp51A modifications, and thus, novel resistance mechanisms are being explored. Here, we characterized two isogenic A. fumigatus clinical strains isolated two years apart from the same patient. Both strains were resistant to clinical azoles but showed different azole resistance mechanisms. One strain (CM8940) harbored a previously described G54A mutation in Cyp51A while the other strain (CM9640) had a novel G457S mutation in Cyp51B, the other target of azoles. In addition, this second strain had a F390L mutation in Hmg1. CM9640 showed higher levels of gene expression of cyp51A, cyp51B and hmg1 than the CM8940 strain. The role of the novel mutation found in Cyp51B together with the contribution of a mutation in Hmg1 in azole resistance is discussed.
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Ghannoum, Mahmoud. "Azole Resistance in Dermatophytes." Journal of the American Podiatric Medical Association 106, no. 1 (January 1, 2016): 79–86. http://dx.doi.org/10.7547/14-109.
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Azole antifungal agents (eg, fluconazole and itraconazole) have been widely used to treat superficial fungal infections caused by dermatophytes and, unlike the allylamines (such as terbinafine and naftifine), have been associated with resistance development. Although many published manuscripts describe resistance to azoles among yeast and molds, reports describing resistance of dermatophytes are starting to appear. In this review, I discuss the mode of action of azole antifungals and mechanisms underlying their resistance compared with the allylamine class of compounds. Data from published and original studies were compared and summarized, and their clinical implications are discussed. In contrast to the cidal allylamines, static drugs such as azoles permit the occurrence of mutations in enzymes involved in ergosterol biosynthesis, and the ergosterol precursors accumulating as a consequence of azole action are not toxic. Azole antifungals, unlike allylamines, potentiate resistance development in dermatophytes.
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Mortensen, Klaus Leth, Emilia Mellado, Cornelia Lass-Flörl, Juan Luis Rodriguez-Tudela, Helle Krogh Johansen, and Maiken Cavling Arendrup. "Environmental Study of Azole-Resistant Aspergillus fumigatus and Other Aspergilli in Austria, Denmark, and Spain." Antimicrobial Agents and Chemotherapy 54, no. 11 (August 30, 2010): 4545–49. http://dx.doi.org/10.1128/aac.00692-10.
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ABSTRACT A single mechanism of azole resistance was shown to predominate in clinical and environmental Aspergillus fumigatus isolates from the Netherlands, and a link to the use of azoles in the environment was suggested. To explore the prevalence of azole-resistant A. fumigatus and other aspergilli in the environment in other European countries, we collected samples from the surroundings of hospitals in Copenhagen, Innsbruck, and Madrid, flowerbeds in an amusement park in Copenhagen, and compost bags purchased in Austria, Denmark, and Spain and screened for azole resistance using multidish agars with itraconazole, voriconazole, and posaconazole. EUCAST method E.DEF 9.1 was used to confirm azole resistance. The promoter and entire coding sequence of the cyp51A gene were sequenced to identify azole-resistant A. fumigatus isolates. A. fumigatus was recovered in 144 out of 185 samples (77.8%). Four A. fumigatus isolates from four Danish soil samples displayed elevated azole MICs (8%), and all harbored the same TR/L98H mutation of cyp51A. One A. lentulus isolate with voriconazole MIC of 4 mg/liter was detected in Spain. No azole-resistant aspergilli were detected in compost. Finally, A. terreus was present in seven samples from Austria. Multi-azole-resistant A. fumigatus is present in the environment in Denmark. The resistance mechanism is identical to that of environmental isolates in the Netherlands. No link to commercial compost could be detected. In Spain and Austria, only Aspergillus species with intrinsic resistance to either azoles or amphotericin B were found.
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Das, Rina, Gyati S. Asthana, Krishan A. Suri, Dinesh Mehta, and Abhay Asthana. "Recent Developments in Azole Compounds as Antitubercular Agent." Mini-Reviews in Organic Chemistry 16, no. 3 (January 25, 2019): 290–306. http://dx.doi.org/10.2174/1570193x15666180622144414.
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Tuberculosis (TB) is a global health disaster and is a wide-reaching hitch. The improper use of antibiotics in chemotherapy of TB patients led to the current problem of tuberculosis therapy which gives rise to Multi-Drug Resistant (MDR) strains. Nitrogen heterocycles including azole compounds are an important class of therapeutic agent with electron-rich property. Azole-based derivatives easily bind with the enzymes and receptors in organisms through noncovalent interactions, thereby possessing various applications in medicinal chemistry. Research on azoles derivatives have been expansively carried out and have become one of the extremely active area in recent years and the progress is quite rapid. A genuine attempt to review chemistry of azoles and to describe various azole-based compounds synthesized in the last two decades having promising antitubercular potential is described in the present article. It is hopeful that azole compounds may continue to serve as an important direction for the exploitation of azole-based antitubercular drugs with better curative effect, lower toxicity, less side effects, especially fewer resistances and so on.
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Meis, Jacques F., Anuradha Chowdhary, Johanna L. Rhodes, Matthew C. Fisher, and Paul E. Verweij. "Clinical implications of globally emerging azole resistance in Aspergillus fumigatus." Philosophical Transactions of the Royal Society B: Biological Sciences 371, no. 1709 (December 5, 2016): 20150460. http://dx.doi.org/10.1098/rstb.2015.0460.
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Aspergillus fungi are the cause of an array of diseases affecting humans, animals and plants. The triazole antifungal agents itraconazole, voriconazole, isavuconazole and posaconazole are treatment options against diseases caused by Aspergillus . However, resistance to azoles has recently emerged as a new therapeutic challenge in six continents. Although de novo azole resistance occurs occasionally in patients during azole therapy, the main burden is the aquisition of resistance through the environment. In this setting, the evolution of resistance is attributed to the widespread use of azole-based fungicides. Although ubiquitously distributed, A. fumigatus is not a phytopathogen. However, agricultural fungicides deployed against plant pathogenic moulds such as Fusarium , Mycospaerella and A. flavus also show activity against A. fumigatus in the environment and exposure of non-target fungi is inevitable. Further, similarity in molecule structure between azole fungicides and antifungal drugs results in cross-resistance of A. fumigatus to medical azoles. Clinical studies have shown that two-thirds of patients with azole-resistant infections had no previous history of azole therapy and high mortality rates between 50% and 100% are reported in azole-resistant invasive aspergillosis. The resistance phenotype is associated with key mutations in the cyp51A gene, including TR 34 /L98H, TR 53 and TR 46 /Y121F/T289A resistance mechanisms. Early detection of resistance is of paramount importance and if demonstrated, either with susceptibility testing or through molecular analysis, azole monotherapy should be avoided. Liposomal amphotericin B or a combination of voriconazole and an echinocandin are recomended for azole-resistant aspergillosis. This article is part of the themed issue ‘Tackling emerging fungal threats to animal health, food security and ecosystem resilience’.
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Jiang, Zi-Yu, Zhe-Yao Huang, Hong Yang, Lin Zhou, Qing-Han Li, and Zhi-Gang Zhao. "Cs2CO3 catalyzed direct aza-Michael addition of azoles to α,β-unsaturated malonates." RSC Advances 12, no. 30 (2022): 19265–69. http://dx.doi.org/10.1039/d2ra02314h.
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A highly efficient method for the synthesis of azole derivatives via a direct aza-Michael addition of azoles to α,β-unsaturated malonates has been successfully developed. A series of azole derivatives have been obtained in up to 94% yield.
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Wang, Kangji, Zhenying Zhang, Xi Chen, Xianyun Sun, Cheng Jin, Hongwei Liu, and Shaojie Li. "Transcription Factor ADS-4 Regulates Adaptive Responses and Resistance to Antifungal Azole Stress." Antimicrobial Agents and Chemotherapy 59, no. 9 (June 22, 2015): 5396–404. http://dx.doi.org/10.1128/aac.00542-15.
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ABSTRACTAzoles are commonly used as antifungal drugs or pesticides to control fungal infections in medicine and agriculture. Fungi adapt to azole stress by rapidly activating the transcription of a number of genes, and transcriptional increases in some azole-responsive genes can elevate azole resistance. The regulatory mechanisms that control transcriptional responses to azole stress in filamentous fungi are not well understood. This study identified a bZIP transcription factor, ADS-4 (antifungaldrugsensitive-4), as a new regulator of adaptive responses and resistance to antifungal azoles. Transcription ofads-4inNeurospora crassacells increased when they were subjected to ketoconazole treatment, whereas the deletion ofads-4resulted in hypersensitivity to ketoconazole and fluconazole. In contrast, the overexpression ofads-4increased resistance to fluconazole and ketoconazole inN. crassa. Transcriptome sequencing (RNA-seq) analysis, followed by quantitative reverse transcription (qRT)-PCR confirmation, showed that ADS-4 positively regulated the transcriptional responses of at least six genes to ketoconazole stress inN. crassa. The gene products of four ADS-4-regulated genes are known contributors to azole resistance, including the major efflux pump CDR4 (Pdr5p ortholog), an ABC multidrug transporter (NcAbcB), sterol C-22 desaturase (ERG5), and a lipid transporter (NcRTA2) that is involved in calcineurin-mediated azole resistance. Deletion of theads-4-homologous gene Afads-4inAspergillus fumigatuscaused hypersensitivity to itraconazole and ketoconazole, which suggested that ADS-4 is a functionally conserved regulator of adaptive responses to azoles. This study provides important information on a new azole resistance factor that could be targeted by a new range of antifungal pesticides and drugs.
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Vazquez, J. A., M. T. Arganoza, J. K. Vaishampayan, and R. A. Akins. "In vitro interaction between amphotericin B and azoles in Candida albicans." Antimicrobial Agents and Chemotherapy 40, no. 11 (November 1996): 2511–16. http://dx.doi.org/10.1128/aac.40.11.2511.
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The use of azole prophylaxis as a measure to prevent invasive fungal infections in high-risk patients is increasing and is now the standard of care in many institutions. Previous studies disagree on whether preexposure of Candida albicans to azoles affects their subsequent susceptibility to amphotericin B (AmB). The present in vitro study indicates that azole exposure generates a subpopulation of cells that are not affected by subsequent exposure to AmB. These cells that are phenotypically resistant to AmB tolerated by most cells not exposed to azole. The percentage of cells that convert to phenotypic resistance to AmB varies with the concentration and the azole. Itraconazole is more effective than fluconazole in generating cells that are phenotypically resistant to AmB and that tolerate an otherwise lethal transient exposure to AmB. Until cells that are not exposed to fluconazole are simultaneously challenged with AmB, they are not protected to a significant extent from killing by AmB. Cells that are challenged with continuous exposure to AmB also acquire phenotypic resistance to AmB at increased frequencies by azole preexposure, but this requires that the azole be continuously present during incubation with AmB. In addition, Candida cells taken from mature colonies that are not actively growing are not susceptible to the short-term killing effects of AmB without azole preexposure. The adaptive responses of C. albicans to AmB and potentially other antifungal agents that may result from prior exposure to azoles in vitro or potentially in microenvironments in vivo that induce physiological changes may have major clinical implications.
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Gast, Charles E., Luiz R. Basso, Igor Bruzual, and Brian Wong. "Azole Resistance in Cryptococcus gattii from the Pacific Northwest: Investigation of the Role ofERG11." Antimicrobial Agents and Chemotherapy 57, no. 11 (August 26, 2013): 5478–85. http://dx.doi.org/10.1128/aac.02287-12.
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ABSTRACTCryptococcus gattiiis responsible for an expanding epidemic of serious infections in Western Canada and the Northwestern United States (Pacific Northwest). Some patients with these infections respond poorly to azole antifungals, and high azole MICs have been reported in Pacific NorthwestC. gattii. In this study, multiple azoles (but not amphotericin B) had higher MICs for 25 Pacific NorthwestC. gattiithan for 34 non-Pacific NorthwestC. gattiior 20Cryptococcus neoformansstrains. We therefore examined the roles in azole resistance of overexpression of or mutations in the gene (ERG11) encoding the azole target enzyme.ERG11/ACT1mRNA ratios were higher inC. gattiithan inC. neoformans, but these ratios did not differ in Pacific Northwest and non-Pacific NorthwestC. gattiistrains, nor did they correlate with fluconazole MICs within any group. Three Pacific NorthwestC. gattiistrains with low azole MICs and 2 with high azole MICs had deduced Erg11p sequences that differed at one or more positions from that of the fully sequenced Pacific NorthwestC. gattiistrain R265. However, the azole MICs for conditionalSaccharomyces cerevisiaeerg11mutants expressing the 5 variantERG11s were within 2-fold of the azole MICs forS. cerevisiaeexpressing theERG11gene fromC. gattiiR265, non-Pacific NorthwestC. gattiistrain WM276, orC. neoformansstrains H99 or JEC21. We conclude that neitherERG11overexpression nor variations inERG11coding sequences was responsible for the high azole MICs observed for the Pacific NorthwestC. gattiistrains we studied.
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Henry, Karl W., Joseph T. Nickels, and Thomas D. Edlind. "Upregulation of ERG Genes inCandida Species by Azoles and Other Sterol Biosynthesis Inhibitors." Antimicrobial Agents and Chemotherapy 44, no. 10 (October 1, 2000): 2693–700. http://dx.doi.org/10.1128/aac.44.10.2693-2700.2000.
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ABSTRACT Infections due to Candida albicans are usually treated with azole antifungals such as fluconazole, but treatment failure is not uncommon especially in immunocompromised individuals. Relatedly, in vitro studies demonstrate that azoles are nonfungicidal, with continued growth at strain-dependent rates even at high azole concentrations. We hypothesized that upregulation ofERG11, which encodes the azole target enzyme lanosterol demethylase, contributes to this azole tolerance in Candidaspecies. RNA analysis revealed that ERG11 expression in C. albicans is maximal during logarithmic-phase growth and decreases as the cells approach stationary phase. Incubation with fluconazole, however, resulted in a two- to fivefold increase in ERG11 RNA levels within 2 to 3 h, and this increase was followed by resumption of culture growth.ERG11 upregulation also occurred following treatment with other azoles (itraconazole, ketoconazole, clotrimazole, and miconazole) and was not dependent on the specific medium or pH. Within 1 h of drug removal ERG11 upregulation was reversed. Azole-dependent upregulation was not limited to ERG11: five of five ERG genes tested whose products function upstream and downstream of lanosterol demethylase in the sterol biosynthetic pathway were also upregulated. Similarly, ERG11upregulation occurred following treatment of C. albicanscultures with terbinafine and fenpropimorph, which target other enzymes in the pathway. These data suggest a common mechanism for globalERG upregulation, e.g., in response to ergosterol depletion. Finally, azole-dependent ERG11 upregulation was demonstrated in three additional Candida species (C. tropicalis, C. glabrata, and C. krusei), indicating a conserved response to sterol biosynthesis inhibitors in opportunistic yeasts.
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Burks, Caroline, Alexandria Darby, Luisa Gómez Londoño, Michelle Momany, and Marin T. Brewer. "Azole-resistant Aspergillus fumigatus in the environment: Identifying key reservoirs and hotspots of antifungal resistance." PLOS Pathogens 17, no. 7 (July 29, 2021): e1009711. http://dx.doi.org/10.1371/journal.ppat.1009711.
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Aspergillus fumigatus is an opportunistic human pathogen that causes aspergillosis, a spectrum of environmentally acquired respiratory illnesses. It has a cosmopolitan distribution and exists in the environment as a saprotroph on decaying plant matter. Azoles, which target Cyp51A in the ergosterol synthesis pathway, are the primary class of drugs used to treat aspergillosis. Azoles are also used to combat plant pathogenic fungi. Recently, an increasing number of azole-naive patients have presented with pan-azole–resistant strains of A. fumigatus. The TR34/L98H and TR46/Y121F/T289A alleles in the cyp51A gene are the most common ones conferring pan-azole resistance. There is evidence that these mutations arose in agricultural settings; therefore, numerous studies have been conducted to identify azole resistance in environmental A. fumigatus and to determine where resistance is developing in the environment. Here, we summarize the global occurrence of azole-resistant A. fumigatus in the environment based on available literature. Additionally, we have created an interactive world map showing where resistant isolates have been detected and include information on the specific alleles identified, environmental settings, and azole fungicide use. Azole-resistant A. fumigatus has been found on every continent, except for Antarctica, with the highest number of reports from Europe. Developed environments, specifically hospitals and gardens, were the most common settings where azole-resistant A. fumigatus was detected, followed by soils sampled from agricultural settings. The TR34/L98H resistance allele was the most common in all regions except South America where the TR46/Y121F/T289A allele was the most common. A major consideration in interpreting this survey of the literature is sampling bias; regions and environments that have been extensively sampled are more likely to show greater azole resistance even though resistance could be more prevalent in areas that are under-sampled or not sampled at all. Increased surveillance to pinpoint reservoirs, as well as antifungal stewardship, is needed to preserve this class of antifungals for crop protection and human health.
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Rani, Dimpy, Vandana Garg, and Rohit Dutt. "Anticancer Potential of Azole Containing Marine Natural Products: Current and Future Perspectives." Anti-Cancer Agents in Medicinal Chemistry 21, no. 15 (September 8, 2021): 1957–76. http://dx.doi.org/10.2174/1871520621666210112112422.
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Background: Despite significant advancement in oncology research, cancer still poses one of the leading causes of mortality worldwide. The increased incidences of cancer may be attributed to the limited efficacy and disastrous side effects of conventional therapies like chemotherapy, radiotherapy and surgery. Azole containing medicinal agents are known for plethora of medicinal properties, including anticancer potential. Objective: In this review, we highlighted azole containing natural products with anticancer potential from marine sources. Methods: A comprehensive literature search was performed for writing the review. Updated views about various marine sponges, cyanobacteria, tunicates and microalgae producing azole nucleus containing secondary metabolites with anticancer potential have been discussed. Results: The present article describes the structural, chemical, and biological features of azoles containing natural agents from marine sources with promising anti-cancer potential. Additionally, current challenges and future perspectives of azoles in cancer prevention and treatment are also discussed. Conclusion: This review might encourage scientific community to explore marine sources for developing novel and potent azole containing anti-cancer agents with better safety profile.
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Te Loo, D. M., R. M. van Schie, and P. M. Hoogerbrugge. "Effect of azole antifungal therapy on vincristine toxicity in childhood acute lymphoblastic leukemia." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): 10049. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.10049.
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10049 Background: Vincristine is one of the corner stitches in the treatment of children with acute lymphoblastic leukemia (ALL). Constipation and other peripheral and central neurotoxicities are the most common side effects. Drugs interfering with the metabolism of vincristine might potentiate these side effects. A group of drugs that interact with the metabolism of vincristine are azoles. Several case reports suggest that co-administration of azoles and vincristine lead to increased toxicity. A comparative study exploring toxicity in patients receiving vincristine with and without azoles, is lacking. For this reason, we retrospectively analyzed neurotoxicity induced by vincristine with (n = 20) and without (n = 20) co-administration of azoles in the same patient group. Methods: In total, twenty pediatric patients with de novo ALL were included in this study. Vincristine toxicity was graded retrospectively according to the National Cancer Institute toxicity scale without information considering comedication. Statistical analysis was performed using the Wilcoxon Signed Rank test and McNemar test. Results: Patients receiving vincristine in combination with prophylactic azole treatment experienced significantly more complaints of constipation and peripheral neurotoxicity (P = 0.001 and P< 0.001, respectively). Three patients (15%) treated with azole therapy developed severe toxicity and needed treatment at the pediatric intensive care unit. Vincristine induced CNS toxicity (convulsions, toxic encephalopathy and SIADH) was seen in 6 patients (30%). All these patients were treated with vincristine in combination with an azole. CNS toxicity was not observed in patients receiving vincristine alone (P = 0 .014). Because of severe toxicities, vincristine treatment was significantly reduced (50% of normal dose) in several patients. Conclusions: This study shows that vincristine toxicity is significantly increased when combined with azole treatment and even can be life threatening. Therefore we advise to avoid the combination of azole and vincristine treatment in patients with ALL. No significant financial relationships to disclose.
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Cools, Hans J., Jonathan G. L. Mullins, Bart A. Fraaije, Josie E. Parker, Diane E. Kelly, John A. Lucas, and Steven L. Kelly. "Impact of Recently Emerged Sterol 14α-Demethylase (CYP51) Variants of Mycosphaerella graminicola on Azole Fungicide Sensitivity." Applied and Environmental Microbiology 77, no. 11 (April 8, 2011): 3830–37. http://dx.doi.org/10.1128/aem.00027-11.
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ABSTRACTThe progressive decline in the effectiveness of some azole fungicides in controllingMycosphaerella graminicola, causal agent of the damagingSeptorialeaf blotch disease of wheat, has been correlated with the selection and spread in the pathogen population of specific mutations in theM. graminicola CYP51(MgCYP51) gene encoding the azole target sterol 14α-demethylase. Recent studies have suggested that the emergence of novel MgCYP51 variants, often harboring substitution S524T, has contributed to a decrease in the efficacy of prothioconazole and epoxiconazole, the two currently most effective azole fungicides againstM. graminicola. In this study, we establish which amino acid alterations in novel MgCYP51 variants have the greatest impact on azole sensitivity and protein function. We introduced individual and combinations of identified alterations by site-directed mutagenesis and functionally determined their impact on azole sensitivity by expression in aSaccharomyces cerevisiaemutant YUG37::erg11carrying a regulatable promoter controlling nativeCYP51expression. We demonstrate that substitution S524T confers decreased sensitivity to all azoles when introduced alone or in combination with Y461S. In addition, S524T restores the function inS. cerevisiaeof MgCYP51 variants carrying the otherwise lethal alterations Y137F and V136A. Sensitivity tests ofS. cerevisiaetransformants expressing recently emerged MgCYP51 variants carrying combinations of alterations D134G, V136A, Y461S, and S524T reveal a substantial impact on sensitivity to the currently most widely used azoles, including epoxiconazole and prothioconazole. Finally, we exploit a recently developed model of the MgCYP51 protein to predict that the substantial structural changes caused by these novel combinations reduce azole interactions with critical residues in the binding cavity, thereby causing resistance.
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Warrilow, Andrew G. S., Nadja Melo, Claire M. Martel, Josie E. Parker, W. David Nes, Steven L. Kelly, and Diane E. Kelly. "Expression, Purification, and Characterization of Aspergillus fumigatus Sterol 14-α Demethylase (CYP51) Isoenzymes A and B." Antimicrobial Agents and Chemotherapy 54, no. 10 (July 26, 2010): 4225–34. http://dx.doi.org/10.1128/aac.00316-10.
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ABSTRACT Aspergillus fumigatus sterol 14-α demethylase (CYP51) isoenzymes A (AF51A) and B (AF51B) were expressed in Escherichia coli and purified. The dithionite-reduced CO-P450 complex for AF51A was unstable, rapidly denaturing to inactive P420, in marked contrast to AF51B, where the CO-P450 complex was stable. Type I substrate binding spectra were obtained with purified AF51B using lanosterol (Ks , 8.6 μM) and eburicol (Ks , 22.6 μM). Membrane suspensions of AF51A bound to both lanosterol (Ks , 3.1 μM) and eburicol (Ks , 4.1 μM). The binding of azoles, with the exception of fluconazole, to AF51B was tight, with the Kd (dissociation constant) values for clotrimazole, itraconazole, posaconazole, and voriconazole being 0.21, 0.06, 0.12, and 0.42 μM, respectively, in comparison with a Kd value of 4 μM for fluconazole. Characteristic type II azole binding spectra were obtained with AF51B, whereas an additional trough and a blue-shifted spectral peak were present in AF51A binding spectra for all azoles except clotrimazole. This suggests two distinct azole binding conformations within the heme prosthetic group of AF51A. All five azoles bound relatively weakly to AF51A, with Kd values ranging from 1 μM for itraconazole to 11.9 μM for fluconazole. The azole binding properties of purified AF51A and AF51B suggest an explanation for the intrinsic azole (fluconazole) resistance observed in Aspergillus fumigatus.
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Müller, Frank-Michael C., Andrea Staudigel, Stefanie Salvenmoser, Antje Tredup, Rudolf Miltenberger, and Josef V. Herrmann. "Cross-Resistance to Medical and Agricultural Azole Drugs in Yeasts from the Oropharynx of Human Immunodeficiency Virus Patients and from Environmental Bavarian Vine Grapes." Antimicrobial Agents and Chemotherapy 51, no. 8 (June 4, 2007): 3014–16. http://dx.doi.org/10.1128/aac.00459-07.
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ABSTRACT Cross-resistance among Candida albicans isolates from the oropharynges of human immunodeficiency virus-infected patients (n = 16) and environmental yeast strains of various species (n = 54) to medical and agricultural azole drugs was observed. Precautions against the unnecessary widespread use of azoles in the environment and human medicine are strongly recommended to prevent patients from acquiring azole-resistant yeasts.
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Leepattarakit, Teera, Orawan Tulyaprawat, and Popchai Ngamskulrungroj. "The Risk Factors and Mechanisms of Azole Resistance of Candida tropicalis Blood Isolates in Thailand: A Retrospective Cohort Study." Journal of Fungi 8, no. 10 (September 20, 2022): 983. http://dx.doi.org/10.3390/jof8100983.
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In recent decades, an epidemiological shift has been observed from Candida infections to non-albicans species and resistance to azoles. We investigated the associated factors and molecular mechanisms of azole-resistant blood isolates of C. tropicalis. Full-length sequencing of the ERG11 gene and quantitative real-time RT-PCR for the ERG11, MDR1, and CDR1 genes were performed. Male sex (odds ratio, 0.38), leukemia (odds ratio 3.15), and recent administration of azole (odds ratio 10.56) were associated with isolates resistant to azole. ERG11 mutations were found in 83% of resistant isolates, with A395T as the most common mutation (53%). There were no statistically significant differences in the expression of the ERG11, MDR1, and CDR1 genes between the groups resistant and susceptible to azole. The prevalence of azole-resistant isolates was higher than the usage of antifungal drugs, suggesting the possibility of environmental transmission in the healthcare setting. The unknown mechanism of the other 17% of the resistant isolates remains to be further investigated.
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Sun, Xianyun, Kangji Wang, Xinxu Yu, Jie Liu, Hanxing Zhang, Fucai Zhou, Baogui Xie, and Shaojie Li. "Transcription Factor CCG-8 as a New Regulator in the Adaptation to Antifungal Azole Stress." Antimicrobial Agents and Chemotherapy 58, no. 3 (December 16, 2013): 1434–42. http://dx.doi.org/10.1128/aac.02244-13.
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ABSTRACTAntifungal azoles are widely used for controlling fungal infections. Fungi are able to change the expression of many genes when they adapt to azole stress, and increased expression of some of these genes can elevate resistance to azoles. However, the regulatory mechanisms behind transcriptional adaption to azoles in filamentous fungi are poorly understood. In this study, we found that deletion of the transcription factor geneccg-8, which is known to be a clock-controlled gene, madeNeurospora crassahypersensitive to azoles. A comparative genome-wide analysis of the responses to ketoconazole of the wild type and theccg-8mutant revealed that the transcriptional responses to ketoconazole of 78 of the 488 transcriptionally ketoconazole-upregulated genes and the 427 transcriptionally ketoconazole-downregulated genes in the wild type were regulated by CCG-8. Ketoconazole sensitivity testing of all available knockout mutants for CCG-8-regulated genes revealed that CCG-8 contributed to azole adaption by regulating the ketoconazole responses of many genes, including the target gene (erg11), an azole transporter gene (cdr4), a hexose transporter gene (hxt13), a stress response gene (locus number NCU06317, namedkts-1), two transcription factor genes (NCU01386 [namedkts-2] andfsd-1/ndt80), four enzyme-encoding genes, and six unknown-function genes. CCG-8 also regulated phospholipid synthesis inN. crassain a manner similar to that of its homolog inSaccharomyces cerevisiae, Opi1p. However, there was no cross talk between phospholipid synthesis and azole resistance inN. crassa. CCG-8 homologs are conserved and are common in filamentous fungi. Deletion of the CCG-8 homolog-encoding gene inFusarium verticillioides(Fvccg-8) also made this fungus hypersensitive to antifungal azoles.
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Jain, Pooja, Indira Akula, and Thomas Edlind. "Cyclic AMP Signaling Pathway Modulates Susceptibility of Candida Species and Saccharomyces cerevisiae to Antifungal Azoles and Other Sterol Biosynthesis Inhibitors." Antimicrobial Agents and Chemotherapy 47, no. 10 (October 2003): 3195–201. http://dx.doi.org/10.1128/aac.47.10.3195-3201.2003.
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ABSTRACT Azoles are widely used antifungals; however, their efficacy is compromised by fungistatic activity and selection of resistant strains during treatment. Recent studies demonstrated roles for the protein kinase C and calcium signaling pathways in modulating azole activity. Here we explored a role for the signaling pathway mediated by cyclic AMP (cAMP), which is synthesized by the regulated action of adenylate cyclase (encoded by CDC35 in Candida albicans and CYR1 in Saccharomyces cerevisiae) and cyclase-associated protein (encoded by CAP1 and SRV2, respectively). Relative to wild-type strains, C. albicans and S. cerevisiae strains mutated in these genes were hypersusceptible to fluconazole (>4- to >16-fold-decreased 48-h MIC), itraconazole (>8- to >64-fold), or miconazole (16- to >64-fold). Similarly, they were hypersusceptible to terbinafine and fenpropimorph (2- to >16-fold), which, like azoles, inhibit sterol biosynthesis. Addition of cAMP to the medium at least partially reversed the hypersusceptibility of Ca-cdc35 and Sc-cyr1-2 mutants. An inhibitor of mammalian adenylate cyclase, MDL-12330A, was tested in combination with azoles; a synergistic effect was observed against azole-susceptible and -resistant strains of C. albicans and five of six non-C. albicans Candida species. Analysis of cAMP levels after glucose induction in the presence and absence of MDL-12330A confirmed that it acts by inhibiting cAMP synthesis in yeast. RNA analysis suggested that a defect in azole-dependent upregulation of the multidrug transporter gene CDR1 contributes to the hypersusceptibility of the Ca-cdc35 mutant. Our results implicate cAMP signaling in the yeast azole response; compounds similar to MDL-12330A may be useful adjuvants in azole therapy.
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Brun, Sophie, Christophe Aubry, Osana Lima, Robert Filmon, Thierry Bergès, Dominique Chabasse, and Jean-Philippe Bouchara. "Relationships between Respiration and Susceptibility to Azole Antifungals in Candida glabrata." Antimicrobial Agents and Chemotherapy 47, no. 3 (March 2003): 847–53. http://dx.doi.org/10.1128/aac.47.3.847-853.2003.
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ABSTRACT Over the past two decades, the incidence of infections due to Candida glabrata, a yeast with intrinsic low susceptibility to azole antifungals, has increased markedly. Respiratory deficiency due to mutations in mitochondrial DNA (mtDNA) associated with resistance to azoles frequently occurs in vitro in this species. In order to specify the relationships between respiration and azole susceptibility, the effects of respiratory chain inhibitors on a wild-type isolate of C. glabrata were evaluated. Respiration of blastoconidia was immediately blocked after extemporaneous addition of potassium cyanide, whereas a 4-h preincubation was required for sodium azide. Antifungal susceptibility determined by a disk diffusion method on Casitone agar containing sodium azide showed a significant decrease in the susceptibility to azoles. Biweekly subculturing on Casitone agar supplemented with sodium azide was therefore performed. This resulted after 40 passages in the isolation of a respiration-deficient mutant, as suggested by its lack of growth on glycerol-containing agar. This respiratory deficiency was confirmed by flow cytometric analysis of blastoconidia stained with rhodamine 123 and by oxygraphy. Moreover, transmission electron microscopy and restriction endonuclease analysis of the mtDNA of mutant cells demonstrated the mitochondrial origin of the respiratory deficiency. Finally, this mutant exhibited cross-resistance to all the azoles tested. In conclusion, blockage of respiration in C. glabrata induces decreased susceptibility to azoles, culminating in azole resistance due to the deletion of mtDNA. This mechanism could explain the induction of petite mutations by azole antifungals which have been demonstrated to act directly on the mitochondrial respiratory chain.
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Borgeat, Valentin, Danielle Brandalise, Frédéric Grenouillet, and Dominique Sanglard. "Participation of the ABC Transporter CDR1 in Azole Resistance of Candida lusitaniae." Journal of Fungi 7, no. 9 (September 15, 2021): 760. http://dx.doi.org/10.3390/jof7090760.
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Candida lusitaniae is an opportunistic pathogen in humans that causes infrequent but difficult-to-treat diseases. Antifungal drugs are used in the clinic to treat C. lusitaniae infections, however, this fungus can rapidly acquire antifungal resistance to all known antifungal drugs (multidrug resistance). C. lusitaniae acquires azole resistance by gain-of-function (GOF) mutations in the transcriptional regulator MRR1. MRR1 controls the expression of a major facilitator transporter (MFS7) that is important for fluconazole resistance. Here, we addressed the role of the ATP Binding Cassette (ABC) transporter CDR1 as additional mediator of azole resistance in C. lusitaniae. CDR1 expression in isolates with GOF MRR1 mutations was higher compared to wild types, which suggests that CDR1 is an additional (direct or indirect) target of MRR1. CDR1 deletion in the azole-resistant isolate P3 (V688G GOF) revealed that MICs of long-tailed azoles, itraconazole and posaconazole, were decreased compared to P3, which is consistent with the role of this ABC transporter in the efflux of these azoles. Fluconazole MIC was only decreased when CDR1 was deleted in the background of an mfs7Δ mutant from P3, which underpins the dominant role of MFS7 in the resistance of the short-tailed azole fluconazole. With R6G efflux readout as Cdr1 efflux capacity, our data showed that R6G efflux was increased in P3 compared to an azole-susceptible wild type parent, and diminished to background levels in mutant strains lacking CDR1. Milbemycin oxim A3, a known inhibitor of fungal ABC transporters, mimicked efflux phenotypes of cdr1Δ mutants. We therefore provided evidence that CDR1 is an additional mediator of azole resistance in C. lusitaniae, and that CDR1 regulation is dependent on MRR1 and associated GOF mutations.
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Marín-Luna, Marta, Rosa M. Claramunt, José Elguero, and Ibon Alkorta. "Theoretical and Spectroscopic Characterization of API-Related Azoles in Solution and in Solid State." Current Pharmaceutical Design 26, no. 38 (October 27, 2020): 4847–57. http://dx.doi.org/10.2174/1381612826666200818212846.
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Azoles are a family of five-membered azacyclic compounds with relevant biological and pharmacological activity. Different subclasses of azoles are defined depending on the atomic arrangement and the number of nitrogen atoms present in the ring: pyrazoles, indazoles, imidazoles, benzimidazoles, triazoles, benzotriazoles, tetrazoles and pentazoles. The complete characterization of their structure and the knowledge about their crystal packing and physical and chemical properties are of vital importance for the advancement in the design of new azole-containing drugs. In this review, we report the latest recent contributions to azole chemistry, in particular, those in which theoretical studies have been performed.
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Steier, Zoë, John-Paul Vermitsky, Geoffrey Toner, Scott E. Gygax, Thomas Edlind, and Santosh Katiyar. "Flucytosine Antagonism of Azole Activity versus Candida glabrata: Role of Transcription Factor Pdr1 and Multidrug Transporter Cdr1." Antimicrobial Agents and Chemotherapy 57, no. 11 (August 26, 2013): 5543–47. http://dx.doi.org/10.1128/aac.02394-12.
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ABSTRACTInfections with the opportunistic yeastCandida glabratahave increased dramatically in recent years. Antifungal therapy of yeast infections commonly employs azoles, such as fluconazole (FLC), butC. glabratafrequently develops resistance to these inhibitors of ergosterol biosynthesis. The pyrimidine analog flucytosine (5-fluorocytosine [5FC]) is highly active versusC. glabratabut is now rarely used clinically due to similar concerns over resistance and, a related concern, the toxicity associated with high doses used to counter resistance. Azole-5FC combination therapy would potentially address these concerns; however, previous studies suggest that 5FC may antagonize azole activity versusC. glabrata. Here, we report that 5FC at subinhibitory concentrations antagonized the activity of FLC 4- to 16-fold versus 8 of 8C. glabrataisolates tested. 5FC antagonized the activity of other azoles similarly but had only indifferent effects in combination with unrelated antifungals. Since azole resistance inC. glabrataresults from transcription factor Pdr1-dependent upregulation of the multidrug transporter geneCDR1, we reasoned that 5FC antagonism might be similarly mediated. Indeed, 5FC-FLC antagonism was abrogated inpdr1Δ andcdr1Δ strains. In further support of this hypothesis, 5FC exposure inducedCDR1expression 6-fold, and this upregulation was Pdr1 dependent. In contrast to azoles, 5FC is not a Cdr1 substrate and so its activation of Pdr1 was unexpected. We observed, however, that 5FC exposure readily induced petite mutants, which exhibit Pdr1-dependentCDR1upregulation. Thus, mitochondrial dysfunction resulting in Pdr1 activation is the likely basis for 5FC antagonism of azole activity versusC. glabrata.
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Duong, Tra My N., Phuong Tuyen Nguyen, Thanh Van Le, Huong Lan P. Nguyen, Bich Ngoc T. Nguyen, Bich Phuong T. Nguyen, Thu Anh Nguyen, et al. "Drug-Resistant Aspergillus flavus Is Highly Prevalent in the Environment of Vietnam: A New Challenge for the Management of Aspergillosis?" Journal of Fungi 6, no. 4 (November 18, 2020): 296. http://dx.doi.org/10.3390/jof6040296.
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The burden of aspergillosis, especially Chronic Pulmonary Aspergillosis, is increasingly recognized, and the increasing presence of azole-resistant environmental Aspergillus fumigatus has been highlighted as a health risk. However, a sizable minority of aspergillosis is caused by Aspergillus flavus, which is assumed to be sensitive to azoles but is infrequently included in surveillance. We conducted environmental sampling at 150 locations in a rural province of southern Vietnam. A. flavus isolates were identified morphologically, their identity was confirmed by sequencing of the beta-tubulin gene, and then they were tested for susceptibility to azoles and amphotericin B according to EUCAST methodologies. We found that over 85% of A. flavus isolates were resistant to at least one azole, and half of them were resistant to itraconazole. This unexpectedly high prevalence of resistance demands further investigation to determine whether it is linked to agricultural azole use, as has been described for A. fumigatus. Clinical correlation is required, so that guidelines can be adjusted to take this information into account.
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Casali, Agnes Kiesling, and Júnia Soares Hamdan. "Effects of three azole derivatives on the lipids of different strains ofSporothrix schenckii." Canadian Journal of Microbiology 43, no. 12 (December 1, 1997): 1197–202. http://dx.doi.org/10.1139/m97-169.
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The comparative effects of ketoconazole, itraconazole, and fluconazole on the lipids of five Sporothrix schenckii strains were investigated. Quantitative analysis of lipids and sterols was completed, as well as qualitative analysis of sterols, by thin-layer chromatography and ultraviolet spectrophotometry. Growth of the S. schenckii isolates in the presence of azole derivative concentrations below the minimum inhibitory concentration (MIC) resulted in significant alterations in the lipid and sterol contents as compared with the control values. Furthermore, lanosterol was detected in these azole-treated cells. These results were in complete agreement with the proposed mechanism of action of azoles, which act by inhibiting ergosterol biosynthesis with a consequent accumulation of lanosterol. Concerning the MIC values, fluconazole was found to be the least effective drug. On the other hand, as determined from a comparison of the effects of the three azoles on the sterol content of the strains studied, no significant differences in efficacy were found among the tested drugs.Key words: Sporothrix schenckii, azole derivatives, lipids, sterols.
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Silva, A. P., I. M. Miranda, A. Guida, J. Synnott, R. Rocha, R. Silva, A. Amorim, C. Pina-Vaz, G. Butler, and A. G. Rodrigues. "Transcriptional Profiling of Azole-Resistant Candida parapsilosis Strains." Antimicrobial Agents and Chemotherapy 55, no. 7 (April 25, 2011): 3546–56. http://dx.doi.org/10.1128/aac.01127-10.
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ABSTRACTHerein we describe the changes in the gene expression profile ofCandida parapsilosisassociated with the acquisition of experimentally induced resistance to azole antifungal drugs. Three resistant strains ofC. parapsilosiswere obtained following prolongedin vitroexposure of a susceptible clinical isolate to constant concentrations of fluconazole, voriconazole, or posaconazole. We found that after incubation with fluconazole or voriconazole, strains became resistant to both azoles but not to posaconazole, although susceptibility to this azole decreased, whereas the strain incubated with posaconazole displayed resistance to the three azoles. The resistant strains obtained after exposure to fluconazole and to voriconazole have increased expression of the transcription factorMRR1, the major facilitator transporterMDR1, and several reductases and oxidoreductases. Interestingly, and similarly to what has been described inC. albicans, upregulation ofMRR1andMDR1is correlated with point mutations inMRR1in the resistant strains. The resistant strain obtained after exposure to posaconazole shows upregulation of two transcription factors (UPC2andNDT80) and increased expression of 13 genes involved in ergosterol biosynthesis. This is the first study addressing global molecular mechanisms underlying azole resistance inC. parapsilosis; the results suggest that similarly toC. albicans, tolerance to azoles involves the activation of efflux pumps and/or increased ergosterol synthesis.
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Jørgensen, Karin Meinike, Marie Helleberg, Rasmus Krøger Hare, Lise Nistrup Jørgensen, and Maiken Cavling Arendrup. "Dissection of the Activity of Agricultural Fungicides against Clinical Aspergillus Isolates with and without Environmentally and Medically Induced Azole Resistance." Journal of Fungi 7, no. 3 (March 11, 2021): 205. http://dx.doi.org/10.3390/jof7030205.
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Azole resistance is an emerging problem in patients with aspergillosis. The role of fungicides for resistance development and occurrence is not fully elucidated. EUCAST reference MICs of 17 fungicides (11 azoles and 6 others), five azole fungicide metabolites and four medical triazoles were examined against two reference and 28 clinical isolates of A. fumigatus, A. flavus and A. terreus with (n = 12) and without (n = 16) resistance mutations. Eight/11 azole fungicides were active against wild-type A. fumigatus, A. flavus and A. terreus, including four (metconazole, prothioconazole-desthio, prochloraz and imazalil) with low MIC50 (≤2 mg/L) against all three species and epoxiconazole, propiconazole, tebuconazole and difenoconazole also against wild-type A. terreus. Mefentrifluconazole, azole metabolites and non-azole fungicides MICs were >16 mg/L against A. fumigatus although partial growth inhibition was found with mefentrifluconazole. Moreover, mefentrifluconazole and axozystrobin were active against wild-type A. terreus. Increased MICs (≥3 dilutions) were found for TR34/L98H, TR34(3)/L98H, TR46/Y121F/T289A and G432S compared to wild-type A. fumigatus for epoxiconazole, propiconazole, tebuconazole, difenoconazole, prochloraz, imazalil and metconazole (except G432S), and for prothioconazole-desthio against TR46/Y121F/T289A, specifically. Increased MICs were found in A. fumigatus harbouring G54R, M220K and M220R alterations for five, one and one azole fungicides, respectively, compared to MICs against wild-type A. fumigatus. Similarly, increased MICs wer found for A. terreus with G51A, M217I and Y491H alterations for five, six and two azole fungicides, respectively. Azole fungicides showed activity against wild-type A. fumigatus, A. terreus and A. flavus, but not against all mutant isolates, suggesting the environmental route of azole resistance may have a role for all three species.
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Zhang, Hui-Zhen, Ponmani Jeyakkumar, Kannekanti Vijaya Kumar, and Cheng-He Zhou. "Synthesis of novel sulfonamide azoles via C–N cleavage of sulfonamides by azole ring and relational antimicrobial study." New Journal of Chemistry 39, no. 7 (2015): 5776–96. http://dx.doi.org/10.1039/c4nj01932f.
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Ding, Wen, Shaoyu Mai, and Qiuling Song. "Molecular-oxygen-promoted Cu-catalyzed oxidative direct amidation of nonactivated carboxylic acids with azoles." Beilstein Journal of Organic Chemistry 11 (November 11, 2015): 2158–65. http://dx.doi.org/10.3762/bjoc.11.233.
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A copper-catalyzed oxidative direct formation of amides from nonactivated carboxylic acids and azoles with dioxygen as an activating reagent is reported. The azole amides were produced in good to excellent yields with a broad substrate scope. The mechanistic studies reveal that oxygen plays an essential role in the success of the amidation reactions with copper peroxycarboxylate as the key intermediate. Transamidation occurs smoothly between azole amide and a variety of amines.
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Nevonen, Dustin E., Laura S. Ferch, Victor Y. Chernii, David E. Herbert, Johan van Lierop, and Victor N. Nemykin. "X-Ray structures, Mössbauer hyperfine parameters, and molecular orbital descriptions of the phthalocyaninato iron(II) azole complexes." Journal of Porphyrins and Phthalocyanines 24, no. 05n07 (May 2020): 894–903. http://dx.doi.org/10.1142/s1088424619502043.
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The electronic structures of a set of PcFe(azole)2 complexes (azole = imidazole, [Formula: see text]-methylimidazole, pyrazole, isoxazole, thiazole, 1,2,4-triazole, 3-amino-1,2,4,-triazole, and 5-amino-1,2,3,4-tetrazole) were examined by Mössbauer spectroscopy and Density Functional Theory (DFT) calculations. In addition, the geometric distortions in these compounds were elucidated by X-ray crystallography for imidazole, pyrazole, and thiazole-containing compounds. Predicted by DFT calculations, Mössbauer hyperfine parameters for all compounds are in reasonable agreement with experimental results, and the influence of the [Formula: see text]-donor and [Formula: see text]-acceptor properties of the axial azoles on the electronic structure of the PcFe(azole)2 complexes is demonstrated by comparison with the reference PcFePy2 compound.
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Chen, Xuebing, Youzhi Wu, Jinyi Xu, Hequan Yao, Aijun Lin, and Yue Huang. "Rh(iii)-catalyzed cyclization reaction of azoles with alkynes: efficient synthesis of azole-fused-pyridines." Organic & Biomolecular Chemistry 13, no. 35 (2015): 9186–89. http://dx.doi.org/10.1039/c5ob01338k.
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Jemel, Sana, Jacques Guillot, Kalthoum Kallel, Grégory Jouvion, Elise Brisebard, Eliane Billaud, Vincent Jullien, Françoise Botterel, and Eric Dannaoui. "In Vivo Efficacy of Voriconazole in a Galleria mellonella Model of Invasive Infection Due to Azole-Susceptible or Resistant Aspergillus fumigatus Isolates." Journal of Fungi 7, no. 12 (November 26, 2021): 1012. http://dx.doi.org/10.3390/jof7121012.
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Aspergillus fumigatus is an environmental filamentous fungus responsible for life-threatening infections in humans and animals. Azoles are the first-line treatment for aspergillosis, but in recent years, the emergence of azole resistance in A. fumigatus has changed treatment recommendations. The objective of this study was to evaluate the efficacy of voriconazole (VRZ) in a Galleria mellonella model of invasive infection due to azole-susceptible or azole-resistant A. fumigatus isolates. We also sought to describe the pharmacokinetics of VRZ in the G. mellonella model. G. mellonella larvae were infected with conidial suspensions of azole-susceptible and azole-resistant isolates of A. fumigatus. Mortality curves were used to calculate the lethal dose. Assessment of the efficacy of VRZ or amphotericin B (AMB) treatment was based on mortality in the lethal model and histopathologic lesions. The pharmacokinetics of VRZ were determined in larval hemolymph. Invasive fungal infection was obtained after conidial inoculation. A dose-dependent reduction in mortality was observed after antifungal treatment with AMB and VRZ. VRZ was more effective at treating larvae inoculated with azole-susceptible A. fumigatus isolates than larvae inoculated with azole-resistant isolates. The concentration of VRZ was maximal at the beginning of treatment and gradually decreased in the hemolymph to reach a Cmin (24 h) between 0.11 and 11.30 mg/L, depending on the dose. In conclusion, G. mellonella is a suitable model for testing the efficacy of antifungal agents against A. fumigatus.
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Reinus, Brandon, and Sean Kerwin. "Preparation and Utility of N-Alkynyl Azoles in Synthesis." Molecules 24, no. 3 (January 24, 2019): 422. http://dx.doi.org/10.3390/molecules24030422.
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Heteroatom-substituted alkynes have attracted a significant amount of interest in the synthetic community due to the polarized nature of these alkynes and their utility in a wide range of reactions. One specific class of heteroatom-substituted alkynes combines this utility with the presence of an azole moiety. These N-alkynyl azoles have been known for nearly 50 years, but recently there has been a tremendous increase in the number of reports detailing the synthesis and utility of this class of compound. While much of the chemistry of N-alkynyl azoles mirrors that of the more extensively studied N-alkynyl amides (ynamides), there are notable exceptions. In addition, as azoles are extremely common in natural products and pharmaceuticals, these N-alkynyl azoles have high potential for accessing biologically important compounds. In this review, the literature reports of N-alkynyl azole synthesis, reactions, and uses have been assembled. Collectively, these reports demonstrate the growth in this area and the promise of exploiting N-alkynyl azoles in synthesis.
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Sun, Lingmei, Shujuan Sun, Aixia Cheng, Xiuzhen Wu, Yu Zhang, and Hongxiang Lou. "In Vitro Activities of Retigeric Acid B Alone and in Combination with Azole Antifungal Agents against Candida albicans." Antimicrobial Agents and Chemotherapy 53, no. 4 (January 26, 2009): 1586–91. http://dx.doi.org/10.1128/aac.00940-08.
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ABSTRACT The vitro antifungal activity of retigeric acid B (RAB), a pentacyclic triterpenoid from the lichen species Lobaria kurokawae, was evaluated alone and in combination with fluconazole, ketoconazole, and itraconazole against Candida albicans using checkerboard microdilution and time-killing tests. The MICs for RAB against 10 different C. albicans isolates ranged from 8 to 16 μg/ml. A synergistic action of RAB and azole was observed in azole-resistant strains, whereas synergistic or indifferent effects were observed in azole-sensitive strains when interpreted by a separate approach of the fractional inhibitory concentration index and ΔE model (the difference between the predicted and measured fungal growth percentages). In time-killing tests, we used both colony counts and a colorimetric assay to evaluate the combinational antifungal effects of RAB and azoles, which further confirmed their synergistic interactions. These findings suggest that the natural product RAB may play a certain role in increasing the susceptibilities of azole-resistant C. albicans strains.
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Zhou, Haipin, Kuo Gai, Aijun Lin, Jinyi Xu, Xiaoming Wu, and Hequan Yao. "Palladium-catalyzed oxidative cross-coupling of azole-4-carboxylates with indoles: an approach to the synthesis of pimprinine." Organic & Biomolecular Chemistry 13, no. 4 (2015): 1243–48. http://dx.doi.org/10.1039/c4ob01844c.
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Buil, Jochem B., Jos Houbraken, Monique H. Reijers, Jan Zoll, Maurizio Sanguinetti, Jacques F. Meis, Paul E. Verweij, and Willem J. G. Melchers. "Genetic and Phenotypic Characterization of in-Host Developed Azole-Resistant Aspergillus flavus Isolates." Journal of Fungi 7, no. 3 (February 25, 2021): 164. http://dx.doi.org/10.3390/jof7030164.
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Aspergillus flavus is a pathogenic fungal species that can cause pulmonary aspergillosis, and triazole compounds are used for the treatment of these infections. Prolonged exposure to azoles may select for compensatory mutations in the A. flavus genome, resulting in azole resistance. Here, we characterize a series of 11 isogenic A. flavus strains isolated from a patient with pulmonary aspergillosis. Over a period of three months, the initially azole-susceptible strain developed itraconazole and voriconazole resistance. Short tandem repeat analysis and whole-genome sequencing revealed the high genetic relatedness of all isolates, indicating an infection with one single isolate. In contrast, the isolates were macroscopically highly diverse, suggesting an adaptation to the environment due to (epi)genetic changes. The whole-genome sequencing of susceptible and azole-resistant strains showed a number of mutations that might be associated with azole resistance. The majority of resistant strains contain a Y119F mutation in the Cyp51A gene, which corresponds to the Y121F mutation found in A. fumigatus. One azole-resistant strain demonstrated a divergent set of mutations, including a V99A mutation in a major facilitator superfamily (MSF) multidrug transporter (AFLA 083950).
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Toepfer, Stephanie, Michaela Lackner, Mikhail V. Keniya, and Brian C. Monk. "Functional Expression of Recombinant Candida auris Proteins in Saccharomyces cerevisiae Enables Azole Susceptibility Evaluation and Drug Discovery." Journal of Fungi 9, no. 2 (January 27, 2023): 168. http://dx.doi.org/10.3390/jof9020168.
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Candida auris infections are difficult to treat due to acquired drug resistance against one or multiple antifungal drug classes. The most prominent resistance mechanisms in C. auris are overexpression and point mutations in Erg11, and the overexpression of efflux pump genes CDR1 and MDR1. We report the establishment of a novel platform for molecular analysis and drug screening based on acquired azole-resistance mechanisms found in C. auris. Constitutive functional overexpression of wild-type C. auris Erg11, Erg11 with amino acid substitutions Y132F or K143R and the recombinant efflux pumps Cdr1 and Mdr1 has been achieved in Saccharomyces cerevisiae. Phenotypes were evaluated for standard azoles and the tetrazole VT-1161. Overexpression of CauErg11 Y132F, CauErg11 K143R, and CauMdr1 conferred resistance exclusively to the short-tailed azoles Fluconazole and Voriconazole. Strains overexpressing the Cdr1 protein were pan-azole resistant. While CauErg11 Y132F increased VT-1161 resistance, K143R had no impact. Type II binding spectra showed tight azole binding to the affinity-purified recombinant CauErg11 protein. The Nile Red assay confirmed the efflux functions of CauMdr1 and CauCdr1, which were specifically inhibited by MCC1189 and Beauvericin, respectively. CauCdr1 exhibited ATPase activity that was inhibited by Oligomycin. The S. cerevisiae overexpression platform enables evaluation of the interaction of existing and novel azole drugs with their primary target CauErg11 and their susceptibility to drug efflux.
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Rosam, Katharina, Brian C. Monk, and Michaela Lackner. "Sterol 14α-Demethylase Ligand-Binding Pocket-Mediated Acquired and Intrinsic Azole Resistance in Fungal Pathogens." Journal of Fungi 7, no. 1 (December 22, 2020): 1. http://dx.doi.org/10.3390/jof7010001.
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The fungal cytochrome P450 enzyme sterol 14α-demethylase (SDM) is a key enzyme in the ergosterol biosynthesis pathway. The binding of azoles to the active site of SDM results in a depletion of ergosterol, the accumulation of toxic intermediates and growth inhibition. The prevalence of azole-resistant strains and fungi is increasing in both agriculture and medicine. This can lead to major yield loss during food production and therapeutic failure in medical settings. Diverse mechanisms are responsible for azole resistance. They include amino acid (AA) substitutions in SDM and overexpression of SDM and/or efflux pumps. This review considers AA affecting the ligand-binding pocket of SDMs with a primary focus on substitutions that affect interactions between the active site and the substrate and inhibitory ligands. Some of these interactions are particularly important for the binding of short-tailed azoles (e.g., voriconazole). We highlight the occurrence throughout the fungal kingdom of some key AA substitutions. Elucidation of the role of these AAs and their substitutions may assist drug design in overcoming some common forms of innate and acquired azole resistance.
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Henry, Karl W., Joseph T. Nickels, and Thomas D. Edlind. "ROX1 and ERG Regulation in Saccharomyces cerevisiae: Implications for Antifungal Susceptibility." Eukaryotic Cell 1, no. 6 (December 2002): 1041–44. http://dx.doi.org/10.1128/ec.1.6.1041-1044.2002.
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ABSTRACT Yeasts respond to treatment with azoles and other sterol biosynthesis inhibitors by upregulating the expression of the ERG genes responsible for ergosterol production. Previous studies on Saccharomyces cerevisiae implicated the ROX1 repressor in ERG regulation. We report that ROX1 deletion resulted in 2.5- to 16-fold-lower susceptibilities to azoles and terbinafine. In untreated cultures, ERG11 was maximally expressed in mid-log phase and expression decreased in late log phase, while the inverse was observed for ROX1. In azole-treated cultures, ERG11 upregulation was preceded by a decrease in ROX1 RNA. These inverse correlations suggest that transcriptional regulation of ROX1 is an important determinant of ERG expression and hence of azole and terbinafine susceptibilities.
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Whaley, Sarah G., Kelly E. Caudle, John-Paul Vermitsky, Sean G. Chadwick, Geoffrey Toner, Katherine S. Barker, Scott E. Gygax, and P. David Rogers. "UPC2AIs Required for High-Level Azole Antifungal Resistance in Candida glabrata." Antimicrobial Agents and Chemotherapy 58, no. 8 (May 27, 2014): 4543–54. http://dx.doi.org/10.1128/aac.02217-13.
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ABSTRACTCandida glabrata, the second most common cause ofCandidainfections, is associated with high rates of mortality and often exhibits resistance to the azole class of antifungal agents. Upc2 and Ecm22 inSaccharomyces cerevisiaeand Upc2 inCandida albicansare the transcriptional regulators ofERG11, the gene encoding the target of azoles in the ergosterol biosynthesis pathway. Recently two homologs for these transcription factors,UPC2AandUPC2B, were identified inC. glabrata. One of these,UPC2A, was shown to influence azole susceptibility. We hypothesized that due to the global role for Upc2 in sterol biosynthesis inS. cerevisiaeandC. albicans, disruption ofUPC2Awould enhance the activity of fluconazole in both azole-susceptible dose-dependent (SDD) and -resistantC. glabrataclinical isolates. To test this hypothesis, we constructed mutants with disruptions inUPC2AandUPC2Balone and in combination in a matched pair of clinical azole-SDD and -resistant isolates. Disruption ofUPC2Ain both the SDD and resistant isolates resulted in increased susceptibility to sterol biosynthesis inhibitors, including a reduction in fluconazole MIC and minimum fungicidal concentration, enhanced azole activity by time-kill analysis, a decrease in ergosterol content, and downregulation of baseline and inducible expression of several sterol biosynthesis genes. Our results indicate that Upc2A is a key regulator of ergosterol biosynthesis and is essential for resistance to sterol biosynthesis inhibitors inC. glabrata. Therefore, theUPC2Apathway may represent a potential cotherapeutic target for enhancing azole activity against this organism.
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Graham, Danyon O., Rajni K. Wilson, Yasmeen N. Ruma, Mikhail V. Keniya, Joel D. A. Tyndall, and Brian C. Monk. "Structural Insights into the Azole Resistance of the Candida albicans Darlington Strain Using Saccharomyces cerevisiae Lanosterol 14α-Demethylase as a Surrogate." Journal of Fungi 7, no. 11 (October 24, 2021): 897. http://dx.doi.org/10.3390/jof7110897.
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Target-based azole resistance in Candida albicans involves overexpression of the ERG11 gene encoding lanosterol 14α-demethylase (LDM), and/or the presence of single or multiple mutations in this enzyme. Overexpression of Candida albicans LDM (CaLDM) Y132H I471T by the Darlington strain strongly increased resistance to the short-tailed azoles fluconazole and voriconazole, and weakly increased resistance to the longer-tailed azoles VT-1161, itraconazole and posaconazole. We have used, as surrogates, structurally aligned mutations in recombinant hexahistidine-tagged full-length Saccharomyces cerevisiae LDM6×His (ScLDM6×His) to elucidate how differential susceptibility to azole drugs is conferred by LDM of the C. albicans Darlington strain. The mutations Y140H and I471T were introduced, either alone or in combination, into ScLDM6×His via overexpression of the recombinant enzyme from the PDR5 locus of an azole hypersensitive strain of S. cerevisiae. Phenotypes and high-resolution X-ray crystal structures were determined for the surrogate enzymes in complex with representative short-tailed (voriconazole) and long-tailed (itraconazole) triazoles. The preferential high-level resistance to short-tailed azoles conferred by the ScLDM Y140H I471T mutant required both mutations, despite the I471T mutation conferring only a slight increase in resistance. Crystal structures did not detect changes in the position/tilt of the heme co-factor of wild-type ScLDM, I471T and Y140H single mutants, or the Y140H I471T double-mutant. The mutant threonine sidechain in the Darlington strain CaLDM perturbs the environment of the neighboring C-helix, affects the electronic environment of the heme, and may, via differences in closure of the neck of the substrate entry channel, increase preferential competition between lanosterol and short-tailed azole drugs.
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Henry, Karl W., M. Cristina Cruz, Santosh K. Katiyar, and Thomas D. Edlind. "Antagonism of Azole Activity against Candida albicans following Induction of Multidrug Resistance Genes by Selected Antimicrobial Agents." Antimicrobial Agents and Chemotherapy 43, no. 8 (August 1, 1999): 1968–74. http://dx.doi.org/10.1128/aac.43.8.1968.
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ABSTRACT Antifungal azoles (e.g., fluconazole) are widely used for prophylaxis or treatment of Candida albicans infections in immunocompromised individuals, such as those with AIDS. These individuals are frequently treated with a variety of additional antimicrobial agents. Potential interactions between three azoles and 16 unrelated drugs (antiviral, antibacterial, antifungal, and antiprotozoal agents) were examined in vitro. Two compounds, tested at concentrations achievable in serum, demonstrated an antagonistic effect on azole activity against C. albicans. At fluconazole concentrations two to four times the 50% inhibitory concentration,C. albicans growth (relative to treatment with fluconazole alone) increased 3- to 18-fold in the presence of albendazole (2 μg/ml) or sulfadiazine (50 μg/ml). Antagonism (3- to 78-fold) of ketoconazole and itraconazole activity by these compounds was also observed. Since azole resistance has been correlated with overexpression of genes encoding efflux proteins, we hypothesized that antagonism results from drug-induced overexpression of these same genes. Indeed, brief incubation of C. albicans with albendazole or sulfadiazine resulted in a 3-to->10-fold increase in RNAs encoding multidrug transporter Cdr1p or Cdr2p. Zidovudine, trimethoprim, and isoniazid, which were not antagonistic with azoles, did not induce these RNAs. Fluphenazine, a known substrate for Cdr1p and Cdr2p, strongly induced their RNAs and, consistent with our hypothesis, strongly antagonized azole activity. Finally, antagonism was shown to require a functional Cdr1p. The possibility that azole activity against C. albicans is antagonized in vivo as well as in vitro in the presence of albendazole and sulfadiazine warrants investigation. Drug-induced overexpression of efflux proteins represents a new and potentially general mechanism for drug antagonism.
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Sanglard, Dominique, Francoise Ischer, and Jacques Bille. "Role of ATP-Binding-Cassette Transporter Genes in High-Frequency Acquisition of Resistance to Azole Antifungals in Candida glabrata." Antimicrobial Agents and Chemotherapy 45, no. 4 (April 1, 2001): 1174–83. http://dx.doi.org/10.1128/aac.45.4.1174-1183.2001.
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ABSTRACT Candida glabrata has been often isolated from AIDS patients with oropharyngeal candidiasis treated with azole antifungal agents, especially fluconazole. We recently showed that the ATP-binding-cassette (ABC) transporter gene CgCDR1 was upregulated in C. glabrata clinical isolates resistant to azole antifungal agents (D. Sanglard, F. Ischer, D. Calabrese, P. A. Majcherczyk, and J. Bille, Antimicrob. Agents Chemother. 43:2753–2765, 1999). Deletion of CgCDR1 in C. glabrata rendered the null mutant hypersusceptible to azole derivatives and showed the importance of this gene in mediating azole resistance. We observed that wild-type C. glabrata exposed to fluconazole in a medium containing the drug at 50 μg/ml developed resistance to this agent and other azoles at a surprisingly high frequency (2 × 10−4 to 4 × 10−4). We show here that this high-frequency azole resistance (HFAR) acquired in vitro was due, at least in part, to the upregulation ofCgCDR1. The CgCDR1 deletion mutant DSY1041 could still develop HFAR but in a medium containing fluconazole at 5 μg/ml. In the HFAR strain derived from DSY1041, a distinct ABC transporter gene similar to CgCDR1, calledCgCDR2, was upregulated. This gene was slightly expressed in clinical isolates but was upregulated in strains with the HFAR phenotype. Deletion of both CgCDR1 and CgCDR2suppressed the development of HFAR in a medium containing fluconazole at 5 μg/ml, showing that both genes are important mediators of resistance to azole derivatives in C. glabrata. We also show here that the HFAR phenomenon was linked to the loss of mitochondria in C. glabrata. Mitochondrial loss could be obtained by treatment with ethidium bromide and resulted in acquisition of resistance to azole derivatives without previous exposure to these agents. Azole resistance obtained in vitro by HFAR or by agents stimulating mitochondrial loss was at least linked to the upregulation of both CgCDR1 and CgCDR2.
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Romero, Mercedes, Fernando Messina, Emmanuel Marin, Alicia Arechavala, Roxana Depardo, Laura Walker, Ricardo Negroni, and Gabriela Santiso. "Antifungal Resistance in Clinical Isolates of Aspergillus spp.: When Local Epidemiology Breaks the Norm." Journal of Fungi 5, no. 2 (May 21, 2019): 41. http://dx.doi.org/10.3390/jof5020041.
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Aspergillosis is a set of very frequent and widely distributed opportunistic diseases. Azoles are the first choice for most clinical forms. However, the distribution of azole-resistant strains is not well known around the world, especially in developing countries. The aim of our study was to determine the proportion of non-wild type strains among the clinical isolates of Aspergillus spp. To this end, the minimum inhibitory concentration of three azoles and amphotericin B (used occasionally in severe forms) was studied by broth microdilution. Unexpectedly, it was found that 8.1% of the isolates studied have a diminished susceptibility to itraconazole. This value turned out to be similar to the highest azole resistance rate reported in different countries across the world.