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Journal articles on the topic 'Antimicrobial peptide resistance'
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1
Browne, Katrina, Sudip Chakraborty, Renxun Chen, Mark DP Willcox, David StClair Black, William R. Walsh, and Naresh Kumar. "A New Era of Antibiotics: The Clinical Potential of Antimicrobial Peptides." International Journal of Molecular Sciences 21, no. 19 (September 24, 2020): 7047. http://dx.doi.org/10.3390/ijms21197047.
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Antimicrobial resistance is a multifaceted crisis, imposing a serious threat to global health. The traditional antibiotic pipeline has been exhausted, prompting research into alternate antimicrobial strategies. Inspired by nature, antimicrobial peptides are rapidly gaining attention for their clinical potential as they present distinct advantages over traditional antibiotics. Antimicrobial peptides are found in all forms of life and demonstrate a pivotal role in the innate immune system. Many antimicrobial peptides are evolutionarily conserved, with limited propensity for resistance. Additionally, chemical modifications to the peptide backbone can be used to improve biological activity and stability and reduce toxicity. This review details the therapeutic potential of peptide-based antimicrobials, as well as the challenges needed to overcome in order for clinical translation. We explore the proposed mechanisms of activity, design of synthetic biomimics, and how this novel class of antimicrobial compound may address the need for effective antibiotics. Finally, we discuss commercially available peptide-based antimicrobials and antimicrobial peptides in clinical trials.
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Jung, Sook-In, Jonathan S. Finkel, Norma V. Solis, Siyang Chaili, Aaron P. Mitchell, Michael R. Yeaman, and Scott G. Filler. "Bcr1 Functions Downstream of Ssd1 To Mediate Antimicrobial Peptide Resistance in Candida albicans." Eukaryotic Cell 12, no. 3 (January 11, 2013): 411–19. http://dx.doi.org/10.1128/ec.00285-12.
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ABSTRACTIn order to colonize the host and cause disease,Candida albicansmust avoid being killed by host defense peptides. Previously, we determined that the regulatory protein Ssd1 governs antimicrobial peptide resistance inC. albicans. Here, we sought to identify additional genes whose products govern susceptibility to antimicrobial peptides. We discovered that abcr1Δ/Δ mutant, like thessd1Δ/Δ mutant, had increased susceptibility to the antimicrobial peptides, protamine, RP-1, and human β defensin-2. Homozygous deletion ofBCR1in thessd1Δ/Δ mutant did not result in a further increase in antimicrobial peptide susceptibility. Exposure of thebcr1Δ/Δ andssd1Δ/Δ mutants to RP-1 induced greater loss of mitochondrial membrane potential and increased plasma membrane permeability than with the control strains. Therefore, Bcr1 and Ssd1 govern antimicrobial peptide susceptibility and likely function in the same pathway. Furthermore,BCR1mRNA expression was downregulated in thessd1Δ/Δ mutant, and the forced expression ofBCR1in thessd1Δ/Δ mutant partially restored antimicrobial peptide resistance. These results suggest that Bcr1 functions downstream of Ssd1. Interestingly, overexpression of 11 known Bcr1 target genes in thebcr1Δ/Δ mutant failed to restore antimicrobial peptide resistance, suggesting that other Bcr1 target genes are likely responsible for antimicrobial peptide resistance. Collectively, these results demonstrate that Bcr1 functions downstream of Ssd1 to govern antimicrobial peptide resistance by maintaining mitochondrial energetics and reducing membrane permeabilization.
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Bachrach, Gilad, Hamutal Altman, Paul E. Kolenbrander, Natalia I. Chalmers, Michal Gabai-Gutner, Amram Mor, Michael Friedman, and Doron Steinberg. "Resistance of Porphyromonas gingivalis ATCC 33277 to Direct Killing by Antimicrobial Peptides Is Protease Independent." Antimicrobial Agents and Chemotherapy 52, no. 2 (December 17, 2007): 638–42. http://dx.doi.org/10.1128/aac.01271-07.
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ABSTRACT Antimicrobial peptides are short, positively charged, amphipathic peptides that possess a wide spectrum of antimicrobial activity and have an important role in the host's innate immunity. Lack of, or dysfunctions in, antimicrobial peptides have been correlated with infectious diseases, including periodontitis. Porphyromonas gingivalis, a gram-negative anaerobe and a major pathogen associated with periodontal diseases, is resistant to antimicrobial peptides of human and nonhuman origin, a feature that likely contributes to its virulence. Expressing a robust proteolytic activity, P. gingivalis hydrolyzes antimicrobial peptides. In this study, P. gingivalis inactivated three antimicrobial peptides, while a d-enantiomer was resistant to degradation. P. gingivalis was resistant to the protease-resistant d-enantiomer peptide, and importantly, a protease-deficient P. gingivalis mutant was also resistant to the antimicrobial peptide. Finally, the binding of a fluorescently labeled antimicrobial peptide to protease-deficient P. gingivalis was much weaker than the binding of susceptible Escherichia coli. Our results suggest that the resistance of P. gingivalis ATCC 33277 to direct killing by antimicrobial peptides is protease independent and results (at least partially) from the low affinity of antimicrobial peptides to P. gingivalis.
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Fernández, Lucía, W. James Gooderham, Manjeet Bains, Joseph B. McPhee, Irith Wiegand, and Robert E. W. Hancock. "Adaptive Resistance to the “Last Hope” Antibiotics Polymyxin B and Colistin in Pseudomonas aeruginosa Is Mediated by the Novel Two-Component Regulatory System ParR-ParS." Antimicrobial Agents and Chemotherapy 54, no. 8 (June 14, 2010): 3372–82. http://dx.doi.org/10.1128/aac.00242-10.
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ABSTRACT As multidrug resistance increases alarmingly, polymyxin B and colistin are increasingly being used in the clinic to treat serious Pseudomonas aeruginosa infections. In this opportunistic pathogen, subinhibitory levels of polymyxins and certain antimicrobial peptides induce resistance toward higher, otherwise lethal, levels of these antimicrobial agents. It is known that the modification of lipid A of lipopolysaccharide (LPS) is a key component of this adaptive peptide resistance, but to date, the regulatory mechanism underlying peptide regulation in P. aeruginosa has remained elusive. The PhoP-PhoQ and PmrA-PmrB two-component systems, which control this modification under low-Mg2+ conditions, do not appear to play a major role in peptide-mediated adaptive resistance, unlike in Salmonella where PhoQ is a peptide sensor. Here we describe the identification and characterization of a novel P. aeruginosa two-component regulator affecting p olymyxin- a daptive r esistance, ParR-ParS (PA1799-PA1798). This system was required for activation of the arnBCADTEF LPS modification operon in the presence of subinhibitory concentrations of polymyxin, colistin, or the bovine peptide indolicidin, leading to increased resistance to various polycationic antibiotics, including aminoglycosides. This study highlights the complexity of the regulatory network controlling resistance to cationic antibiotics and host peptides in P. aeruginosa, which has major relevance in the development and deployment of cationic antimicrobials.
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Bechinger, B., and S. U. Gorr. "Antimicrobial Peptides: Mechanisms of Action and Resistance." Journal of Dental Research 96, no. 3 (November 25, 2016): 254–60. http://dx.doi.org/10.1177/0022034516679973.
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More than 40 antimicrobial peptides and proteins (AMPs) are expressed in the oral cavity. These AMPs have been organized into 6 functional groups, 1 of which, cationic AMPs, has received extensive attention in recent years for their promise as potential antibiotics. The goal of this review is to describe recent advances in our understanding of the diverse mechanisms of action of cationic AMPs and the bacterial resistance against these peptides. The recently developed peptide GL13K is used as an example to illustrate many of the discussed concepts. Cationic AMPs typically exhibit an amphipathic conformation, which allows increased interaction with negatively charged bacterial membranes. Peptides undergo changes in conformation and aggregation state in the presence of membranes; conversely, lipid conformation and packing can adapt to the presence of peptides. As a consequence, a single peptide can act through several mechanisms depending on the peptide’s structure, the peptide:lipid ratio, and the properties of the lipid membrane. Accumulating evidence shows that in addition to acting at the cell membrane, AMPs may act on the cell wall, inhibit protein folding or enzyme activity, or act intracellularly. Therefore, once a peptide has reached the cell wall, cell membrane, or its internal target, the difference in mechanism of action on gram-negative and gram-positive bacteria may be less pronounced than formerly assumed. While AMPs should not cause widespread resistance due to their preferential attack on the cell membrane, in cases where specific protein targets are involved, the possibility exists for genetic mutations and bacterial resistance. Indeed, the potential clinical use of AMPs has raised the concern that resistance to therapeutic AMPs could be associated with resistance to endogenous host-defense peptides. Current evidence suggests that this is a rare event that can be overcome by subtle structural modifications of an AMP.
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Gank, Kimberly D., Michael R. Yeaman, Satoshi Kojima, Nannette Y. Yount, Hyunsook Park, John E. Edwards, Scott G. Filler, and Yue Fu. "SSD1 Is Integral to Host Defense Peptide Resistance in Candida albicans." Eukaryotic Cell 7, no. 8 (May 30, 2008): 1318–27. http://dx.doi.org/10.1128/ec.00402-07.
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ABSTRACT Candida albicans is usually a harmless human commensal. Because inflammatory responses are not normally induced by colonization, antimicrobial peptides are likely integral to first-line host defense against invasive candidiasis. Thus, C. albicans must have mechanisms to tolerate or circumvent molecular effectors of innate immunity and thereby colonize human tissues. Prior studies demonstrated that an antimicrobial peptide-resistant strain of C. albicans, 36082R, is hypervirulent in animal models versus its susceptible counterpart (36082S). The current study aimed to identify a genetic basis for antimicrobial peptide resistance in C. albicans. Screening of a C. albicans genomic library identified SSD1 as capable of conferring peptide resistance to a susceptible surrogate, Saccharomyces cerevisiae. Sequencing confirmed that the predicted translation products of 36082S and 36082R SSD1 genes were identical. However, Northern analyses corroborated that SSD1 is expressed at higher levels in 36082R than in 36082S. In isogenic backgrounds, ssd1Δ/ssd1Δ null mutants were significantly more susceptible to antimicrobial peptides than parental strains but had equivalent susceptibilities to nonpeptide stressors. Moreover, SSD1 complementation of ssd1Δ/ssd1Δ mutants restored parental antimicrobial peptide resistance phenotypes, and overexpression of SSD1 conferred enhanced peptide resistance. Consistent with these in vitro findings, ssd1 null mutants were significantly less virulent in a murine model of disseminated candidiasis than were their parental or complemented strains. Collectively, these results indicate that SSD1 is integral to C. albicans resistance to host defense peptides, a phenotype that appears to enhance the virulence of this organism in vivo.
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Chu, Hung-Lun, Hui-Yuan Yu, Bak-Sau Yip, Ya-Han Chih, Chong-Wen Liang, Hsi-Tsung Cheng, and Jya-Wei Cheng. "Boosting Salt Resistance of Short Antimicrobial Peptides." Antimicrobial Agents and Chemotherapy 57, no. 8 (May 28, 2013): 4050–52. http://dx.doi.org/10.1128/aac.00252-13.
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ABSTRACTThe efficacies of many antimicrobial peptides are greatly reduced under high salt concentrations, therefore limiting their use as pharmaceutical agents. Here, we describe a strategy to boost salt resistance and serum stability of short antimicrobial peptides by adding the nonnatural bulky amino acid β-naphthylalanine to their termini. The activities of the short salt-sensitive tryptophan-rich peptide S1 were diminished at high salt concentrations, whereas the activities of its β-naphthylalanine end-tagged variants were less affected.
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Rivas-Santiago, Bruno, Carmen J. Serrano, and J. Antonio Enciso-Moreno. "Susceptibility to Infectious Diseases Based on Antimicrobial Peptide Production." Infection and Immunity 77, no. 11 (August 24, 2009): 4690–95. http://dx.doi.org/10.1128/iai.01515-08.
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ABSTRACT In the last few years, the great impact of antimicrobial peptides on infectious disease susceptibility and natural resistance has been reported. In some cases, susceptibility to diseases is related to antimicrobial peptide polymorphisms and gene copy numbers, but for the vast majority of infectious diseases, these phenomena need to be elucidated. This review is focused on the current knowledge about susceptibility and resistance conferred by genetic variations in antimicrobial peptide expression in infectious diseases.
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Chu, Hung-Lun, Ya-Han Chih, Kuang-Li Peng, Chih-Lung Wu, Hui-Yuan Yu, Doris Cheng, Yu-Ting Chou, and Jya-Wei Cheng. "Antimicrobial Peptides with Enhanced Salt Resistance and Antiendotoxin Properties." International Journal of Molecular Sciences 21, no. 18 (September 16, 2020): 6810. http://dx.doi.org/10.3390/ijms21186810.
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A strategy was described to design antimicrobial peptides (AMPs) with enhanced salt resistance and antiendotoxin activities by linking two helical AMPs with the Ala-Gly-Pro (AGP) hinge. Among the designed peptides, KR12AGPWR6 demonstrated the best antimicrobial activities even in high salt conditions (NaCl ~300 mM) and possessed the strongest antiendotoxin activities. These activities may be related to hydrophobicity, membrane-permeability, and α-helical content of the peptide. Amino acids of the C-terminal helices were found to affect the peptide-induced permeabilization of LUVs, the α-helicity of the designed peptides under various LUVs, and the LPS aggregation and size alternation. A possible model was proposed to explain the mechanism of LPS neutralization by the designed peptides. These findings could provide a new approach for designing AMPs with enhanced salt resistance and antiendotoxin activities for potential therapeutic applications.
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Ribeiro, Ana R. M., Helena P. Felgueiras, Susana P. G. Costa, and Sílvia M. M. A. Pereira-Lima. "Synthesis of Peptaibolin, an Antimicrobial Peptide." Proceedings 78, no. 1 (December 1, 2020): 47. http://dx.doi.org/10.3390/iecp2020-08654.
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To tackle one of the biggest global health problems, the resistance of microorganisms to antibiotics, a collective effort in the search for more effective agents against bacteria was required. Peptides with antimicrobial activity have been raising much attention as a promising alternative for antibiotics. Peptaibols, for instance, are a family of antimicrobial peptides (AMPs) with great biomedical potential, in which the Peptaibolin can be highlighted. This peptide has gained relevance due to its small amino acids content, only four, and its acetyl group and a phenylalaninol residue (Phol) at the N-terminal and C-terminal, respectively. Here, we report the synthesis of Peptaibolin through Solid Phase Peptide Synthesis assisted by Microwave heating (MW-SPPS) in a pre-loaded Phe-Wang resin. Starting from a loading of 0.51 mmol/g, two syntheses were made, using two different combinations of coupling reagents. The best option was DIC/Oxima, achieving a yield of 50.0%. Proton Nuclear Magnetic Resonance (1H-NMR) studies confirmed the peptide structure, while High Performance Liquid Chromatography (HPLC) verified the peptide purity. The peptide solubility was examined against several combinations of solvents. Peptaibolin was not soluble in water, only in organic solvents or in the combination of both. Antimicrobial testing was conducted using Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, and Pseudomonas aeruginosa. Minimum inhibitory concentration studies demonstrated the resistance of bacteria to the peptide action and the peptide instability in bacterial growth conditions.
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Tzeng, Yih-Ling, and David S. Stephens. "Antimicrobial peptide resistance in Neisseria meningitidis." Biochimica et Biophysica Acta (BBA) - Biomembranes 1848, no. 11 (November 2015): 3026–31. http://dx.doi.org/10.1016/j.bbamem.2015.05.006.
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Nava Lara, Rodrigo, Longendri Aguilera-Mendoza, Carlos Brizuela, Antonio Peña, and Gabriel Del Rio. "Heterologous Machine Learning for the Identification of Antimicrobial Activity in Human-Targeted Drugs." Molecules 24, no. 7 (March 31, 2019): 1258. http://dx.doi.org/10.3390/molecules24071258.
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The emergence of microbes resistant to common antibiotics represent a current treat to human health. It has been recently recognized that non-antibiotic labeled drugs may promote antibiotic-resistance mechanisms in the human microbiome by presenting a secondary antibiotic activity; hence, the development of computer-assisted procedures to identify antibiotic activity in human-targeted compounds may assist in preventing the emergence of resistant microbes. In this regard, it is worth noting that while most antibiotics used to treat human infectious diseases are non-peptidic compounds, most known antimicrobials nowadays are peptides, therefore all computer-based models aimed to predict antimicrobials either use small datasets of non-peptidic compounds rendering predictions with poor reliability or they predict antimicrobial peptides that are not currently used in humans. Here we report a machine-learning-based approach trained to identify gut antimicrobial compounds; a unique aspect of our model is the use of heterologous training sets, in which peptide and non-peptide antimicrobial compounds were used to increase the size of the training data set. Our results show that combining peptide and non-peptide antimicrobial compounds rendered the best classification of gut antimicrobial compounds. Furthermore, this classification model was tested on the latest human-approved drugs expecting to identify antibiotics with broad-spectrum activity and our results show that the model rendered predictions consistent with current knowledge about broad-spectrum antibiotics. Therefore, heterologous machine learning rendered an efficient computational approach to classify antimicrobial compounds.
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Lee, Jong-Kook, and Yoonkyung Park. "All d-Lysine Analogues of the Antimicrobial Peptide HPA3NT3-A2 Increased Serum Stability and without Drug Resistance." International Journal of Molecular Sciences 21, no. 16 (August 6, 2020): 5632. http://dx.doi.org/10.3390/ijms21165632.
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Novel antibiotic drugs are urgently needed because of the increase in drug-resistant bacteria. The use of antimicrobial peptides has been suggested to replace antibiotics as they have strong antimicrobial activity and can be extracted from living organisms such as insects, marine organisms, and mammals. HPA3NT3-A2 ([Ala1,8] HPA3NT3) is an antimicrobial peptide that is an analogue of the HP (2–20) peptide derived from Helicobacter pylori ribosomal protein L1. Although this peptide was shown to have strong antimicrobial activity against drug-resistant bacteria, it also showed lower toxicity against sheep red blood cells (RBCs) and HaCaT cells compared to HPA3NT3. The l-Lys residues of HPA3NT3-A2 was substituted with d-Lys residues (HPA3NT3-A2D; [d-Lys2,5,6,9,10,15] HPA3NT3-A2) to prevent the cleavage of peptide bonds by proteolytic enzymes under physiological conditions. This peptide showed an increased half-life and maintained its antimicrobial activity in the serum against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) (pathogen). Furthermore, the antimicrobial activity of HPA3NT3-A2D was not significantly affected in the presence of mono- or divalent ions (Na+, Mg2+, Ca2+). Finally, l- or d-HPA3NT3-A2 peptides exhibited the strongest antimicrobial activity against antibiotic-resistant bacteria and failed to induce resistance in Staphylococcus aureus after 12 passages.
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Oyston, P. C. F., M. A. Fox, S. J. Richards, and G. C. Clark. "Novel peptide therapeutics for treatment of infections." Journal of Medical Microbiology 58, no. 8 (August 1, 2009): 977–87. http://dx.doi.org/10.1099/jmm.0.011122-0.
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As antibiotic resistance increases worldwide, there is an increasing pressure to develop novel classes of antimicrobial compounds to fight infectious disease. Peptide therapeutics represent a novel class of therapeutic agents. Some, such as cationic antimicrobial peptides and peptidoglycan recognition proteins, have been identified from studies of innate immune effector mechanisms, while others are completely novel compounds generated in biological systems. Currently, only selected cationic antimicrobial peptides have been licensed, and only for topical applications. However, research using new approaches to identify novel antimicrobial peptide therapeutics, and new approaches to delivery and improving stability, will result in an increased range of peptide therapeutics available in the clinic for broader applications.
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Kraszewska, Joanna, Michael C. Beckett, Tharappel C. James, and Ursula Bond. "Comparative Analysis of the Antimicrobial Activities of Plant Defensin-Like and Ultrashort Peptides against Food-Spoiling Bacteria." Applied and Environmental Microbiology 82, no. 14 (May 6, 2016): 4288–98. http://dx.doi.org/10.1128/aem.00558-16.
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ABSTRACTAntimicrobial peptides offer potential as novel therapeutics to combat food spoilage and poisoning caused by pathogenic and nonpathogenic bacteria. Our previous studies identified the peptide human beta-defensin 3 (HBD3) as a potent antimicrobial agent against a wide range of beer-spoiling bacteria. Thus, HBD3 is an excellent candidate for development as an additive to prevent food and beverage spoilage. To expand the repertoire of peptides with antimicrobial activity against bacteria associated with food spoilage and/or food poisoning, we carried out anin silicodiscovery pipeline to identify peptides with structure and activity similar to those of HBD3, focusing on peptides of plant origin. Using a standardized assay, we compared the antimicrobial activities of nine defensin-like plant peptides to the activity of HBD3. Only two of the peptides, fabatin-2 and Cp-thionin-2, displayed antimicrobial activity; however, the peptides differed from HBD3 in being sensitive to salt and were thermostable. We also compared the activities of several ultrashort peptides to that of HBD3. One of the peptides, the synthetic tetrapeptide O3TR, displayed biphasic antimicrobial activity but had a narrower host range than HBD3. Finally, to determine if the peptides might act in concert to improve antimicrobial activity, we compared the activities of the peptides in pairwise combinations. The plant defensin-like peptides fabatin-2 and Cp-thionin-2 displayed a synergistic effect with HBD3, while O3TR was antagonistic. Thus, some plant defensin-like peptides are effective antimicrobials and may act in concert with HBD3 to control bacteria associated with food spoilage and food poisoning.IMPORTANCEFood spoilage and food poisoning caused by bacteria can have major health and economic implications for human society. With the rise in resistance to conventional antibiotics, there is a need to identify new antimicrobials to combat these outbreaks in our food supply. Here we screened plant peptide databases to identify peptides that share structural similarity with the human defensin peptide HBD3, which has known antimicrobial activity against food-spoiling bacteria. We show that two of the plant peptides display antimicrobial activity against bacteria associated with food spoilage. When combined with HBD3, the peptides are highly effective. We also analyzed the activity of an easily made ultrashort synthetic peptide, O3TR. We show that this small peptide also displays antimicrobial activity against food-spoiling bacteria but is not as effective as HBD3 or the plant peptides. The plant peptides identified are good candidates for development as natural additives to prevent food spoilage.
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Boparai, Jaspreet Kaur, and Pushpender Kumar Sharma. "Mini Review on Antimicrobial Peptides, Sources, Mechanism and Recent Applications." Protein & Peptide Letters 27, no. 1 (December 10, 2019): 4–16. http://dx.doi.org/10.2174/0929866526666190822165812.
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Antimicrobial peptides in recent years have gained increased interest among scientists, health professionals and the pharmaceutical companies owing to their therapeutic potential. These are low molecular weight proteins with broad range antimicrobial and immuno modulatory activities against infectious bacteria (Gram positive and Gram negative), viruses and fungi. Inability of micro-organisms to develop resistance against most of the antimicrobial peptide has made them as an efficient product which can greatly impact the new era of antimicrobials. In addition to this these peptides also demonstrates increased efficacy, high specificity, decreased drug interaction, low toxicity, biological diversity and direct attacking properties. Pharmaceutical industries are therefore conducting appropriate clinical trials to develop these peptides as potential therapeutic drugs. More than 60 peptide drugs have already reached the market and several hundreds of novel therapeutic peptides are in preclinical and clinical development. Rational designing can be used further to modify the chemical and physical properties of existing peptides. This mini review will discuss the sources, mechanism and recent therapeutic applications of antimicrobial peptides in treatment of infectious diseases.
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Cheung, Gordon YC, and Michael Otto. "Do antimicrobial peptides and antimicrobial-peptide resistance play important roles during bacterial infection?" Future Microbiology 13, no. 10 (August 2018): 1073–75. http://dx.doi.org/10.2217/fmb-2018-0138.
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Nagarajan, Deepesh, Tushar Nagarajan, Neha Nanajkar, and Nagasuma Chandra. "A Uniform In Vitro Efficacy Dataset to Guide Antimicrobial Peptide Design." Data 4, no. 1 (February 10, 2019): 27. http://dx.doi.org/10.3390/data4010027.
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Antimicrobial peptides are ubiquitous molecules that form the innate immune system of organisms across all kingdoms of life. Despite their prevalence and early origins, they continue to remain potent natural antimicrobial agents. Antimicrobial peptides are therefore promising drug candidates in the face of overwhelming multi-drug resistance to conventional antibiotics. Over the past few decades, thousands of antimicrobial peptides have been characterized in vitro, and their efficacy data are now available in a multitude of public databases. Computational antimicrobial peptide design attempts typically use such data. However, utilizing heterogenous data aggregated from different sources presents significant drawbacks. In this report, we present a uniform dataset containing 20 antimicrobial peptides assayed against 30 organisms of Gram-negative, Gram-positive, mycobacterial, and fungal origin. We also present circular dichroism spectra for all antimicrobial peptides. We draw simple inferences from this data, and we discuss what characteristics are essential for antimicrobial peptide efficacy. We expect our uniform dataset to be useful for future projects involving computational antimicrobial peptide design.
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Audrain, Bianca, Lionel Ferrières, Amira Zairi, Guillaume Soubigou, Curtis Dobson, Jean-Yves Coppée, Christophe Beloin, and Jean-Marc Ghigo. "Induction of the Cpx Envelope Stress Pathway Contributes to Escherichia coli Tolerance to Antimicrobial Peptides." Applied and Environmental Microbiology 79, no. 24 (October 4, 2013): 7770–79. http://dx.doi.org/10.1128/aem.02593-13.
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ABSTRACTAntimicrobial peptides produced by multicellular organisms as part of their innate system of defense against microorganisms are currently considered potential alternatives to conventional antibiotics in case of infection by multiresistant bacteria. However, while the mode of action of antimicrobial peptides is relatively well described, resistance mechanisms potentially induced or selected by these peptides are still poorly understood. In this work, we studied the mechanisms of action and resistance potentially induced by ApoEdpL-W, a new antimicrobial peptide derived from human apolipoprotein E. Investigation of the genetic response ofEscherichia coliupon exposure to sublethal concentrations of ApoEdpL-W revealed that this antimicrobial peptide triggers activation of RcsCDB, CpxAR, and σEenvelope stress pathways. This genetic response is not restricted to ApoEdpL-W, since several other antimicrobial peptides, including polymyxin B, melittin, LL-37, and modified S4dermaseptin, also activate severalE. colienvelope stress pathways. Finally, we demonstrate that induction of the CpxAR two-component system directly contributes toE. colitolerance toward ApoEdpL-W, polymyxin B, and melittin. These results therefore show thatE. colisenses and responds to different antimicrobial peptides by activation of the CpxAR pathway. While this study further extends the understanding of the array of peptide-induced stress signaling systems, it also provides insight into the contribution of Cpx envelope stress pathway toE. colitolerance to antimicrobial peptides.
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Lorenzon, Esteban N., Julia P. Piccoli, Norival A. Santos-Filho, and Eduardo M. Cilli. "Dimerization of Antimicrobial Peptides: A Promising Strategy to Enhance Antimicrobial Peptide Activity." Protein & Peptide Letters 26, no. 2 (February 20, 2019): 98–107. http://dx.doi.org/10.2174/0929866526666190102125304.
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Antimicrobial resistance is a global health problem with strong social and economic impacts. The development of new antimicrobial agents is considered an urgent challenge. In this regard, Antimicrobial Peptides (AMPs) appear to be novel candidates to overcome this problem. The mechanism of action of AMPs involves intracellular targets and membrane disruption. Although the exact mechanism of action of AMPs remains controversial, most AMPs act through membrane disruption of the target cell. Several strategies have been used to improve AMP activity, such as peptide dimerization. In this review, we focus on AMP dimerization, showing many examples of dimerized peptides and their effects on biological activity. Although more studies are necessary to elucidate the relationship between peptide properties and the dimerization effect on antimicrobial activity, dimerization constitutes a promising strategy to improve the effectiveness of AMPs.
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Yu, Hui-Yuan, Chih-Hsiung Tu, Bak-Sau Yip, Heng-Li Chen, Hsi-Tsung Cheng, Kuo-Chun Huang, Hsiu-Jung Lo, and Jya-Wei Cheng. "Easy Strategy To Increase Salt Resistance of Antimicrobial Peptides." Antimicrobial Agents and Chemotherapy 55, no. 10 (July 18, 2011): 4918–21. http://dx.doi.org/10.1128/aac.00202-11.
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ABSTRACTThe efficacies of many antimicrobial peptides are greatly reduced under high salt concentrations, limiting their development as pharmaceutical compounds. Here, we describe an easy strategy to increase salt resistance of antimicrobial peptides by replacing tryptophan or histidine residues with the bulky amino acids β-naphthylalanine and β-(4,4′-biphenyl)alanine. The activities of the salt-sensitive peptide P-113 were diminished at high salt concentrations, whereas the activities of its β-naphthylalanine and β-(4,4′-biphenyl)alanine-substituted variant were less affected.
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Yeaman, Michael R., and Nannette Y. Yount. "Mechanisms of Antimicrobial Peptide Action and Resistance." Pharmacological Reviews 55, no. 1 (March 1, 2003): 27–55. http://dx.doi.org/10.1124/pr.55.1.2.
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Tzeng, Yih-Ling, Karita D. Ambrose, Susu Zughaier, Xiaoliu Zhou, Yoon K. Miller, William M. Shafer, and David S. Stephens. "Cationic Antimicrobial Peptide Resistance in Neisseria meningitidis." Journal of Bacteriology 187, no. 15 (August 1, 2005): 5387–96. http://dx.doi.org/10.1128/jb.187.15.5387-5396.2005.
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ABSTRACT Cationic antimicrobial peptides (CAMPs) are important components of the innate host defense system against microbial infections and microbial products. However, the human pathogen Neisseria meningitidis is intrinsically highly resistant to CAMPs, such as polymyxin B (PxB) (MIC ≥ 512 μg/ml). To ascertain the mechanisms by which meningococci resist PxB, mutants that displayed increased sensitivity (≥4-fold) to PxB were identified from a library of mariner transposon mutants generated in a meningococcal strain, NMB. Surprisingly, more than half of the initial PxB-sensitive mutants had insertions within the mtrCDE operon, which encodes proteins forming a multidrug efflux pump. Additional PxB-sensitive mariner mutants were identified from a second round of transposon mutagenesis performed in an mtr efflux pump-deficient background. Further, a mutation in lptA, the phosphoethanolamine (PEA) transferase responsible for modification of the lipid A head groups, was identified to cause the highest sensitivity to PxB. Mutations within the mtrD or lptA genes also increased meningococcal susceptibility to two structurally unrelated CAMPs, human LL-37 and protegrin-1. Consistently, PxB neutralized inflammatory responses elicited by the lptA mutant lipooligosaccharide more efficiently than those induced by wild-type lipooligosaccharide. mariner mutants with increased resistance to PxB were also identified in NMB background and found to contain insertions within the pilMNOPQ operon involved in pilin biogenesis. Taken together, these data indicated that meningococci utilize multiple mechanisms including the action of the MtrC-MtrD-MtrE efflux pump and lipid A modification as well as the type IV pilin secretion system to modulate levels of CAMP resistance. The modification of meningococcal lipid A head groups with PEA also prevents neutralization of the biological effects of endotoxin by CAMP.
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Lorenzón, E. N., G. F. Cespedes, E. F. Vicente, L. G. Nogueira, T. M. Bauab, M. S. Castro, and E. M. Cilli. "Effects of Dimerization on the Structure and Biological Activity of Antimicrobial Peptide Ctx-Ha." Antimicrobial Agents and Chemotherapy 56, no. 6 (March 5, 2012): 3004–10. http://dx.doi.org/10.1128/aac.06262-11.
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ABSTRACTIt is well known that cationic antimicrobial peptides (cAMPs) are potential microbicidal agents for the increasing problem of antimicrobial resistance. However, the physicochemical properties of each peptide need to be optimized for clinical use. To evaluate the effects of dimerization on the structure and biological activity of the antimicrobial peptide Ctx-Ha, we have synthesized the monomeric and three dimeric (Lys-branched) forms of the Ctx-Ha peptide by solid-phase peptide synthesis using a combination of 9-fluorenylmethyloxycarbonyl (Fmoc) andt-butoxycarbonyl (Boc) chemical approaches. The antimicrobial activity assay showed that dimerization decreases the ability of the peptide to inhibit growth of bacteria or fungi; however, the dimeric analogs displayed a higher level of bactericidal activity. In addition, a dramatic increase (50 times) in hemolytic activity was achieved with these analogs. Permeabilization studies showed that the rate of carboxyfluorescein release was higher for the dimeric peptides than for the monomeric peptide, especially in vesicles that contained sphingomyelin. Despite different biological activities, the secondary structure and pore diameter were not significantly altered by dimerization. In contrast to the case for other dimeric cAMPs, we have shown that dimerization selectively decreases the antimicrobial activity of this peptide and increases the hemolytic activity. The results also show that the interaction between dimeric peptides and the cell wall could be responsible for the decrease of the antimicrobial activity of these peptides.
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Nüsslein, Klaus, Lachelle Arnt, Jason Rennie, Cullen Owens, and Gregory N. Tew. "Broad-spectrum antibacterial activity by a novel abiogenic peptide mimic." Microbiology 152, no. 7 (July 1, 2006): 1913–18. http://dx.doi.org/10.1099/mic.0.28812-0.
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The human-mediated use and abuse of classical antibiotics has created a strong selective pressure for the rapid evolution of antibiotic resistance. As resistance levels rise, and the efficacy of classical antibiotics wanes, the intensity of the search for alternative antimicrobials has increased. One class of molecules that has attracted much attention is the antimicrobial peptides (AMPs). They exhibit broad-spectrum activity, they are potent and they are widespread as part of the innate defence system of both vertebrates and invertebrates. However, peptides are complex molecules that suffer from proteolytic degradation. The ability to capture the essential properties of antimicrobial peptides in simple easy-to-prepare molecules that are abiotic in origin and non-proteolytic offers many advantages. Mechanistic and structural knowledge of existing AMPs was used to design a novel compound that mimics the biochemical activity of an AMP. This report describes the development and in vitro characterization of a small peptide mimic that exhibited quick-acting and selective antibacterial activity against a broad range of bacteria, including numerous clinically relevant strains, at low MIC values.
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Ruijne, Fleur, and Oscar P. Kuipers. "Combinatorial biosynthesis for the generation of new-to-nature peptide antimicrobials." Biochemical Society Transactions 49, no. 1 (January 13, 2021): 203–15. http://dx.doi.org/10.1042/bst20200425.
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Natural peptide products are a valuable source of important therapeutic agents, including antibiotics, antivirals and crop protection agents. Aided by an increased understanding of structure–activity relationships of these complex molecules and the biosynthetic machineries that produce them, it has become possible to re-engineer complete machineries and biosynthetic pathways to create novel products with improved pharmacological properties or modified structures to combat antimicrobial resistance. In this review, we will address the progress that has been made using non-ribosomally produced peptides and ribosomally synthesized and post-translationally modified peptides as scaffolds for designed biosynthetic pathways or combinatorial synthesis for the creation of novel peptide antimicrobials.
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Simonson, Andrew W., Matthew R. Aronson, and Scott H. Medina. "Supramolecular Peptide Assemblies as Antimicrobial Scaffolds." Molecules 25, no. 12 (June 14, 2020): 2751. http://dx.doi.org/10.3390/molecules25122751.
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Antimicrobial discovery in the age of antibiotic resistance has demanded the prioritization of non-conventional therapies that act on new targets or employ novel mechanisms. Among these, supramolecular antimicrobial peptide assemblies have emerged as attractive therapeutic platforms, operating as both the bactericidal agent and delivery vector for combinatorial antibiotics. Leveraging their programmable inter- and intra-molecular interactions, peptides can be engineered to form higher ordered monolithic or co-assembled structures, including nano-fibers, -nets, and -tubes, where their unique bifunctionalities often emerge from the supramolecular state. Further advancements have included the formation of macroscopic hydrogels that act as bioresponsive, bactericidal materials. This systematic review covers recent advances in the development of supramolecular antimicrobial peptide technologies and discusses their potential impact on future drug discovery efforts.
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Lin, Yaxian, Siyan Liu, Xinping Xi, Chengbang Ma, Lei Wang, Xiaoling Chen, Zhanzhong Shi, Tianbao Chen, Chris Shaw, and Mei Zhou. "Study on the Structure-Activity Relationship of an Antimicrobial Peptide, Brevinin-2GUb, from the Skin Secretion of Hylarana guentheri." Antibiotics 10, no. 8 (July 22, 2021): 895. http://dx.doi.org/10.3390/antibiotics10080895.
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Antimicrobial peptides (AMPs) are considered potential alternatives to antibiotics due to their advantages in solving antibiotic resistance. Brevinin-2GUb, which was extracted from the skin secretion of Hylarana guentheri, is a peptide with modest antimicrobial activity. Several analogues were designed to explore the structure–activity relationship and enhance its activity. In general, the Rana box is not an indispensable motif for the bioactivity of Brevinin-2GUb, and the first to the 19th amino acids at the N-terminal end are active fragments, such that shortening the peptide while maintaining its bioactivity is a promising strategy for the optimisation of peptides. Keeping a complete hydrophobic face and increasing the net charges are key factors for antimicrobial activity. With the increase of cationic charges, α-helical proportion, and amphipathicity, the activity of t-Brevinin-2GUb-6K (tB2U-6K), in combatting bacteria, drastically improved, especially against Gram-negative bacteria, and the peptide attained the capacity to kill clinical isolates and fungi as well, which made it possible to address some aspects of antibiotic resistance. Thus, peptide tB2U-6K, with potent antimicrobial activity against antibiotic-resistant bacteria, the capacity to inhibit the growth of biofilm, and low toxicity against normal cells, is of value to be further developed into an antimicrobial agent.
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Rinker, Sherri D., Michael P. Trombley, Xiaoping Gu, Kate R. Fortney, and Margaret E. Bauer. "Deletion ofmtrCin Haemophilus ducreyi Increases Sensitivity to Human Antimicrobial Peptides and Activates the CpxRA Regulon." Infection and Immunity 79, no. 6 (March 28, 2011): 2324–34. http://dx.doi.org/10.1128/iai.01316-10.
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ABSTRACTHaemophilus ducreyiresists killing by antimicrobial peptides encountered during human infection, including cathelicidin LL-37, α-defensins, and β-defensins. In this study, we examined the role of the proton motive force-dependent multiple transferable resistance (MTR) transporter in antimicrobial peptide resistance inH. ducreyi. We found a proton motive force-dependent effect onH. ducreyi's resistance to LL-37 and β-defensin HBD-3, but not α-defensin HNP-2. Deletion of the membrane fusion protein MtrC renderedH. ducreyimore sensitive to LL-37 and human β-defensins but had relatively little effect on α-defensin resistance. ThemtrCmutant 35000HPmtrCexhibited phenotypic changes in outer membrane protein profiles, colony morphology, and serum sensitivity, which were restored to wild type bytrans-complementation withmtrC. Similar phenotypes were reported in acpxAmutant; activation of the two-component CpxRA regulator was confirmed by showing transcriptional effects on CpxRA-regulated genes in 35000HPmtrC. AcpxRmutant had wild-type levels of antimicrobial peptide resistance; acpxAmutation had little effect on defensin resistance but led to increased sensitivity to LL-37. 35000HPmtrCwas more sensitive than thecpxAmutant to LL-37, indicating that MTR contributed to LL-37 resistance independent of the CpxRA regulon. The CpxRA regulon did not affect proton motive force-dependent antimicrobial peptide resistance; however, 35000HPmtrChad lost proton motive force-dependent peptide resistance, suggesting that the MTR transporter promotes proton motive force-dependent resistance to LL-37 and human β-defensins. This is the first report of a β-defensin resistance mechanism inH. ducreyiand shows that LL-37 resistance inH. ducreyiis multifactorial.
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Matson, Jyl S., Hyun Ju Yoo, Kristina Hakansson, and Victor J. DiRita. "Polymyxin B Resistance in El Tor Vibrio cholerae Requires Lipid Acylation Catalyzed by MsbB." Journal of Bacteriology 192, no. 8 (February 12, 2010): 2044–52. http://dx.doi.org/10.1128/jb.00023-10.
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ABSTRACTAntimicrobial peptides are critical for innate antibacterial defense. Both Gram-negative and Gram-positive microbes have mechanisms to alter their surfaces and resist killing by antimicrobial peptides. InVibrio cholerae, two natural epidemic biotypes, classical and El Tor, exhibit distinct phenotypes with respect to sensitivity to the peptide antibiotic polymyxin B: classical strains are sensitive and El Tor strains are relatively resistant. We carried out mutant screens of both biotypes, aiming to identify classicalV. choleraemutants resistant to polymyxin B and El TorV. choleraemutants sensitive to polymyxin B. Insertions in a gene annotatedmsbB(encoding a predicted lipid A secondary acyltransferase) answered both screens, implicating its activity in antimicrobial peptide resistance ofV. cholerae. Analysis of a defined mutation in the El Tor biotype demonstrated thatmsbBis required for resistance to all antimicrobial peptides tested. Mutation ofmsbBin a classical strain resulted in reduced resistance to several antimicrobial peptides but in no significant change in resistance to polymyxin B.msbBmutants of both biotypes showed decreased colonization of infant mice, with a more pronounced defect observed for the El Tor mutant. Mass spectrometry analysis showed that lipid A of themsbBmutant for both biotypes was underacylated compared to lipid A of the wild-type isolates, confirming that MsbB is a functional acyltransferase inV. cholerae.
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Fodor, András, Birhan Addisie Abate, Péter Deák, László Fodor, Ervin Gyenge, Michael G. Klein, Zsuzsanna Koncz, et al. "Multidrug Resistance (MDR) and Collateral Sensitivity in Bacteria, with Special Attention to Genetic and Evolutionary Aspects and to the Perspectives of Antimicrobial Peptides—A Review." Pathogens 9, no. 7 (June 29, 2020): 522. http://dx.doi.org/10.3390/pathogens9070522.
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Antibiotic poly-resistance (multidrug-, extreme-, and pan-drug resistance) is controlled by adaptive evolution. Darwinian and Lamarckian interpretations of resistance evolution are discussed. Arguments for, and against, pessimistic forecasts on a fatal “post-antibiotic era” are evaluated. In commensal niches, the appearance of a new antibiotic resistance often reduces fitness, but compensatory mutations may counteract this tendency. The appearance of new antibiotic resistance is frequently accompanied by a collateral sensitivity to other resistances. Organisms with an expanding open pan-genome, such as Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae, can withstand an increased number of resistances by exploiting their evolutionary plasticity and disseminating clonally or poly-clonally. Multidrug-resistant pathogen clones can become predominant under antibiotic stress conditions but, under the influence of negative frequency-dependent selection, are prevented from rising to dominance in a population in a commensal niche. Antimicrobial peptides have a great potential to combat multidrug resistance, since antibiotic-resistant bacteria have shown a high frequency of collateral sensitivity to antimicrobial peptides. In addition, the mobility patterns of antibiotic resistance, and antimicrobial peptide resistance, genes are completely different. The integron trade in commensal niches is fortunately limited by the species-specificity of resistance genes. Hence, we theorize that the suggested post-antibiotic era has not yet come, and indeed might never come.
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Bhopale, Girish M. "Antimicrobial Peptides: A Promising Avenue for Human Healthcare." Current Pharmaceutical Biotechnology 21, no. 2 (February 12, 2020): 90–96. http://dx.doi.org/10.2174/1389201020666191011121722.
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Antimicrobial drugs resistant microbes have been observed worldwide and therefore alternative development of antimicrobial peptides has gained interest in human healthcare. Enormous progress has been made in the development of antimicrobial peptide during the last decade due to major advantages of AMPs such as broad-spectrum activity and low levels of induced resistance over the current antimicrobial agents. This review briefly provides various categories of AMP, their physicochemical properties and mechanism of action which governs their penetration into microbial cell. Further, the recent information on current status of antimicrobial peptide development, their applications and perspective in human healthcare are also described.
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Gebhard, Susanne, Chong Fang, Aishath Shaaly, David J. Leslie, Marion R. Weimar, Falk Kalamorz, Alan Carne, and Gregory M. Cook. "Identification and Characterization of a Bacitracin Resistance Network in Enterococcus faecalis." Antimicrobial Agents and Chemotherapy 58, no. 3 (December 16, 2013): 1425–33. http://dx.doi.org/10.1128/aac.02111-13.
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ABSTRACTResistance ofEnterococcus faecalisagainst antimicrobial peptides, both of host origin and produced by other bacteria of the gut microflora, is likely to be an important factor in the bacterium's success as an intestinal commensal. The aim of this study was to identify proteins with a role in resistance against the model antimicrobial peptide bacitracin. Proteome analysis of bacitracin-treated and untreated cells showed that bacitracin stress induced the expression of cell wall-biosynthetic proteins and caused metabolic rearrangements. Among the proteins with increased production, an ATP-binding cassette (ABC) transporter with similarity to known peptide antibiotic resistance systems was identified and shown to mediate resistance against bacitracin. Expression of the transporter was dependent on a two-component regulatory system and a second ABC transporter, which were identified by genome analysis. Both resistance and the regulatory pathway could be functionally transferred toBacillus subtilis, proving the function and sufficiency of these components for bacitracin resistance. Our data therefore show that the two ABC transporters and the two-component system form a resistance network against antimicrobial peptides inE. faecalis, where one transporter acts as the sensor that activates the TCS to induce production of the second transporter, which mediates the actual resistance.
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Feng, Yang, Yang-Yang Zhang, Ke Li, Na Tian, Wei-Bo Wang, Qian-Xiong Zhou, and Xue-Song Wang. "Photocleavable antimicrobial peptide mimics for precluding antibiotic resistance." New Journal of Chemistry 42, no. 5 (2018): 3192–95. http://dx.doi.org/10.1039/c8nj00015h.
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Kooi, Cora, and Pamela A. Sokol. "Burkholderia cenocepacia zinc metalloproteases influence resistance to antimicrobial peptides." Microbiology 155, no. 9 (September 1, 2009): 2818–25. http://dx.doi.org/10.1099/mic.0.028969-0.
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Burkholderia cenocepacia secretes two zinc-dependent metalloproteases, designated ZmpA and ZmpB. Previously, ZmpA and ZmpB have been shown to cleave several proteins important in host defence. In this study, the ability of ZmpA and ZmpB to digest and inactivate antimicrobial peptides involved in innate immunity was examined. ZmpB but not ZmpA cleaved β-defensin-1. ZmpA but not ZmpB cleaved the cathelicidin LL-37. Both enzymes cleaved elafin and secretory leukocyte inhibitor, which are antimicrobial peptides as well as neutrophil elastase inhibitors. Both ZmpA and ZmpB cleaved protamine, a fish antimicrobial peptide, and a zmpA zmpB mutant was more sensitive to protamine killing than the parental strain. ZmpA or ZmpB cleavage of elafin inactivated its anti-protease activity. The effect of ZmpA and ZmpB on the neutrophil proteases elastase and cathepsin G was also examined but neither enzyme was active against these host proteases. These studies suggest that ZmpA and ZmpB may influence the resistance of B. cenocepacia to host antimicrobial peptides as well as alter the host protease/anti-protease balance in chronic respiratory infections.
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Robles-Fort, Aida, Inmaculada García-Robles, Wasundara Fernando, David W. Hoskin, Carolina Rausell, and María Dolores Real. "Dual Antimicrobial and Antiproliferative Activity of TcPaSK Peptide Derived from a Tribolium castaneum Insect Defensin." Microorganisms 9, no. 2 (January 22, 2021): 222. http://dx.doi.org/10.3390/microorganisms9020222.
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Antimicrobial peptides (AMPs) found in the innate immune system of a wide range of organisms might prove useful to fight infections, due to the reported slower development of resistance to AMPs. Increasing the cationicity and keeping moderate hydrophobicity of the AMPs have been described to improve antimicrobial activity. We previously found a peptide derived from the Tribolium castaneum insect defensin 3, exhibiting antrimicrobial activity against several human pathogens. Here, we analyzed the effect against Staphyloccocus aureus of an extended peptide (TcPaSK) containing two additional amino acids, lysine and asparagine, flanking the former peptide fragment in the original insect defensin 3 protein. TcPaSK peptide displayed higher antimicrobial activity against S. aureus, and additionally showed antiproliferative activity against the MDA-MB-231 triple negative breast cancer cell line. A SWATH proteomic analysis revealed the downregulation of proteins involved in cell growth and tumor progression upon TcPaSK cell treatment. The dual role of TcPaSK peptide as antimicrobial and antiproliferative agent makes it a versatile molecule that warrants exploration for its use in novel therapeutic developments as an alternative approach to overcome bacterial antibiotic resistance and to increase the efficacy of conventional cancer treatments.
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Teng, Qiu-Xu, Xiaofang Luo, Zi-Ning Lei, Jing-Quan Wang, John Wurpel, Zuodong Qin, and Dong-Hua Yang. "The Multidrug Resistance-Reversing Activity of a Novel Antimicrobial Peptide." Cancers 12, no. 7 (July 19, 2020): 1963. http://dx.doi.org/10.3390/cancers12071963.
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The overexpression of ATP-binding cassette (ABC) transporters is a common cause of multidrug resistance (MDR) in cancers. The intracellular drug concentration of cancer cells can be decreased relative to their normal cell counterparts due to increased expression of ABC transporters acting as efflux pumps of anticancer drugs. Over the past decades, antimicrobial peptides have been investigated as a new generation of anticancer drugs and some of them were reported to have interactions with ABC transporters. In this article, we investigated several novel antimicrobial peptides to see if they could sensitize ABCB1-overexpressing cells to the anticancer drugs paclitaxel and doxorubicin, which are transported by ABCB1. It was found that peptide XH-14C increased the intracellular accumulation of ABCB1 substrate paclitaxel, which demonstrated that XH-14C could reverse ABCB1-mediated MDR. Furthermore, XH-14C could stimulate the ATPase activity of ABCB1 and the molecular dynamic simulation revealed a stable binding pose of XH-14C-ABCB1 complex. There was no change on the expression level or the location of ABCB1 transporter with the treatment of XH-14C. Our results suggest that XH-14C in combination with conventional anticancer agents could be used as a novel strategy for cancer treatment.
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Locock, Katherine E. S. "Bioinspired Polymers: Antimicrobial Polymethacrylates." Australian Journal of Chemistry 69, no. 7 (2016): 717. http://dx.doi.org/10.1071/ch16047.
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Naturally occurring antimicrobial peptides have been honed by evolution over millions of years to give highly safe and efficacious antimicrobials that form part of many organisms’ immune systems. By studying these peptides to identify key aspects of structure and composition, suitable synthetic polymer mimics can be designed that hold potential as anti-infective agents. This review focusses on an important aspect of peptide mimicry, that of replicating the chemical functionality provided by key amino acids present in antimicrobial peptides. These include polymethacrylate mimics of arginine-rich and tryptophan-rich peptides. Systematic investigation of the structure–activity relationships of these polymers identifies the guanidine based poly(methylmethacrylate-co-2-guanidinoethyl methacrylate) (pMMA-co-GEMA) copolymers with low molecular weight and low methyl content as having superior activity profiles when compared with all other combinations. Unique antibiofilm activity of these polymers is also revealed in in vitro testing against monomicrobial and polymicrobial biofilms of the bacteria Staphylococcus aureus and the fungus Candida albicans. This highlights Mother Nature as an important resource in drug development and identifies the arginine-mimicking polymethacrylates as important leads for the development of a new generation of antimicrobial agents to tackle resistance.
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Mejía-Argueta, Euridice L., Jonnathan G. Santillán Benítez, and Mariana Ortiz-Reynoso. "Antimicrobial peptides, an alternative to combat bacterial resistance." Acta Biológica Colombiana 25, no. 2 (May 1, 2020): 294–302. http://dx.doi.org/10.15446/abc.v25n2.77407.
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Antimicrobial peptides of higher organisms have been studied for the past 25 years, and their importance as components of innate immunity is now well established. The essential simplicity of their chemical structure, along with the lower likelihood of developed resistance compared to conventional antibiotics, has made them attractive candidates for development as therapeutics. The objective of this review article is to describe the current relevance, main mechanisms presented, and the uses of antimicrobial peptides as new therapies in the clinical area. The information used was mainly compiled from scientific articles based on a systematic review of scientific papers with data on human antimicrobial peptides (AMPs) and their different applications, searching without date limits and only documents in English and Spanish. Gray literature was accessed through manual search, and no restrictions were made involving study design for a retrospective study. Although these products have not yet been commercialized, they have advantages over the currently available treatments since they are not expected to cause bacterial resistance due to their three-dimensional structure, amphipathic tendency, and cationic character; however, the technique of peptide production is still new and is in the early stages of innovation of new molecules.
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McBride, Shonna M., and Abraham L. Sonenshein. "Identification of a Genetic Locus Responsible for Antimicrobial Peptide Resistance inClostridium difficile." Infection and Immunity 79, no. 1 (October 25, 2010): 167–76. http://dx.doi.org/10.1128/iai.00731-10.
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ABSTRACTClostridium difficilecauses chronic intestinal disease, yet little is understood about how the bacterium interacts with and survives in the host. To colonize the intestine and cause persistent disease, the bacterium must circumvent killing by host innate immune factors, such as cationic antimicrobial peptides (CAMPs). In this study, we investigated the effect of model CAMPs on growth and found thatC. difficileis not only sensitive to these compounds but also responds to low levels of CAMPs by expressing genes that lead to CAMP resistance. By plating the bacterium on medium containing the CAMP nisin, we isolated a mutant capable of growing in three times the inhibitory concentration of CAMPs. This mutant also showed increased resistance to the CAMPs gallidermin and polymyxin B, demonstrating tolerance to different types of antimicrobial peptides. We identified the mutated gene responsible for the resistance phenotype as CD1352. This gene encodes a putative orphan histidine kinase that lies adjacent to a predicted ABC transporter operon (CD1349 to CD1351). Transcriptional analysis of the ABC transporter genes revealed that this operon was upregulated in the presence of nisin in wild-type cells and was more highly expressed in the CD1352 mutant. The insertional disruption of the CD1349 gene resulted in significant decreases in resistance to the CAMPs nisin and gallidermin but not polymyxin B. Because of their role in cationic antimicrobial peptide resistance, we propose the designationcprABCfor genes CD1349 to CD1351 andcprKfor the CD1352 gene. These results provide the first evidence of aC. difficilegene associated with antimicrobial peptide resistance.
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Nawrocki, Kathryn, Emily Crispell, and Shonna McBride. "Antimicrobial Peptide Resistance Mechanisms of Gram-Positive Bacteria." Antibiotics 3, no. 4 (October 13, 2014): 461–92. http://dx.doi.org/10.3390/antibiotics3040461.
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Perron, Gabriel G., Michael Zasloff, and Graham Bell. "Experimental evolution of resistance to an antimicrobial peptide." Proceedings of the Royal Society B: Biological Sciences 273, no. 1583 (November 2005): 251–56. http://dx.doi.org/10.1098/rspb.2005.3301.
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LaRock, Christopher N., and Victor Nizet. "Cationic antimicrobial peptide resistance mechanisms of streptococcal pathogens." Biochimica et Biophysica Acta (BBA) - Biomembranes 1848, no. 11 (November 2015): 3047–54. http://dx.doi.org/10.1016/j.bbamem.2015.02.010.
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Musin, Kh G. "ANTIMICROBIAL PEPTIDES — A POTENTIAL REPLACEMENT FOR TRADITIONAL ANTIBIOTICS." Russian Journal of Infection and Immunity 8, no. 3 (November 4, 2018): 295–308. http://dx.doi.org/10.15789/2220-7619-2018-3-295-308.
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Antimicrobial peptides are a heterogeneous group of molecules involved in the innate and acquired immune response of various organisms, ranging from prokaryotes to mammals, including humans. They consist of 12–50 amino acid residues; have different physico-chemical and biological properties. The most common feature is their ability to destroy the prokaryotic cell membrane, which causes cell death. In the action, the molecules of antimicrobial peptides are embedded in the target bacteriological cells and change their conformation, forming structures in some cases resembling channels. Some other molecules of antimicrobial peptides can cover the surface of a bacteriological cell and form a carpet, when they reach a critical mass they act like detergents. In addition, being positively charged molecules of such peptides, penetrating through the membranes of parasitic and bacteriological cells, bind to polyanionic RNA and DNA molecules. Among the benefits of antimicrobial peptides is their high metabolic activity, low probability of occurrence of addictions and side effects. In addition, bacteriological pathogens that previously did not have resistance to any antimicrobial peptide are difficult to develop a strategy to control them. In this connection, these peptides are the most promising moleculessubstitutes for traditional antibiotics. The article discusses the approaches and strategies of therapeutic use, the studies of antimicrobial peptides identified in recent years; The most frequently encountered mechanisms of interaction of antimicrobial peptides and a bacteriological membrane are described, the physicochemical properties of peptide molecules are described; the results of studies on the detection of resistance of some strains of bacteria to antimicrobial peptides and antibiotics in general are summarized.
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Shao, Changxuan, Weizhong Li, Peng Tan, Anshan Shan, Xiujing Dou, Deying Ma, and Chunyu Liu. "Symmetrical Modification of Minimized Dermaseptins to Extend the Spectrum of Antimicrobials with Endotoxin Neutralization Potency." International Journal of Molecular Sciences 20, no. 6 (March 20, 2019): 1417. http://dx.doi.org/10.3390/ijms20061417.
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Antimicrobial peptides (AMPs) have emerged as a promising class of antimicrobial agents that could potentially address the global antibiotic resistance. Generating mirror-like peptides by minimizing dermaseptin family sequences is an effective strategy for designing AMPs. However, the previous research still had some limitations such as lower effectiveness and a narrow spectrum of antibacterial activity. To further expand and hone this strategy, we designed a series of AMPs consisting of the WXMXW-NH2 motif (X represents V, I, F, and W; M represents KAAAKAAAK). The peptides formed α-helices and displayed broad-spectrum antimicrobial activities against eleven types of clinical bacteria including both Gram-negative and Gram-positive bacteria. The optimized peptide WW exhibited high physical rupture by inducing membrane shrinkage, disruption, and lysis. Moreover, WW effectively neutralized endotoxins and inhibited the inflammatory response while having the highest therapeutic index. In conclusion, these results indicated that the peptide WW has potential as a broad-spectrum antimicrobial agent or preservative for overcoming the risk of multidrug resistance in localized or external therapeutic applications.
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Sallum, Ulysses W., and Thomas T. Chen. "Inducible Resistance of Fish Bacterial Pathogens to the Antimicrobial Peptide Cecropin B." Antimicrobial Agents and Chemotherapy 52, no. 9 (May 12, 2008): 3006–12. http://dx.doi.org/10.1128/aac.00023-08.
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ABSTRACT Cecropin B is a cationic antimicrobial peptide originally isolated from the diapausing pupae of the giant silk moth, Hylphora cecropia. Cecropin B elicits its antimicrobial effects through disruption of the anionic cell membranes of gram-negative bacteria. Previous work by our laboratory demonstrated that a constitutively expressed cecropin B transgene conferred enhanced resistance to bacterial infection in medaka. The development of antibiotic resistance by pathogenic bacteria is a growing problem. The potential for fish bacterial pathogens to develop resistance to cecropin B was addressed in this study. Four fish bacterial pathogens were selected for the study based on their importance in aquaculture. Vibrio anguillarum, Vibrio vulnificus, and Yersinia ruckeri all exhibited inducible resistance to cecropin B. The inducible resistance of these three pathogens was correlated with reversible changes in their ultrastructures, as observed by scanning electron microscopy. V. anguillarum was demonstrated to become more adhesive to a CHSE-214 cell monolayer and to cause increased cumulative mortality in medaka following exposure to cecropin B. This work demonstrates that the resistance of fish bacterial pathogens to cecropin B is inducible and suggests that resistance to other cationic antimicrobial peptides may occur through similar means. The observed changes in ultrastructure and infectivity suggest that resistance to antimicrobial peptides is an integral part of the pathogenesis of fish gram-negative bacterial pathogens.
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Mwangi, James, Yizhu Yin, Gan Wang, Min Yang, Ya Li, Zhiye Zhang, and Ren Lai. "The antimicrobial peptide ZY4 combats multidrug-resistantPseudomonas aeruginosaandAcinetobacter baumanniiinfection." Proceedings of the National Academy of Sciences 116, no. 52 (December 16, 2019): 26516–22. http://dx.doi.org/10.1073/pnas.1909585117.
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The emergence of carbapenem-resistantAcinetobacter baumanniiandPseudomonas aeruginosaraises fears of untreatable infections and poses the greatest health threats. Antimicrobial peptides (AMPs) are regarded as the most ideal solution to this menace. In this study, a set of peptides was designed based on our previously reported peptide cathelicidin-BF-15, and the lead peptide ZY4, a cyclic peptide stabilized by a disulfide bridge with high stability in vivo (the half-life is 1.8 h), showed excellent activity againstP. aeruginosaandA. baumannii, including standard and clinical multidrug-resistant (MDR) strains. ZY4 killed bacteria by permeabilizing the bacterial membrane and showed low propensity to induce resistance, exhibited biofilm inhibition and eradication activities, and also killed persister cells. Notably, administration of ZY4 decreased susceptibility to lung infection byP. aeruginosaand suppressed dissemination ofP. aeruginosaandA. baumanniito target organs in a mouse septicemia infection model. These findings identify ZY4 as an ideal candidate against MDR bacterial infections.
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Donini, Marcello, Chiara Lico, Selene Baschieri, Stefania Conti, Walter Magliani, Luciano Polonelli, and Eugenio Benvenuto. "Production of an Engineered Killer Peptide in Nicotiana benthamiana by Using a Potato virus X Expression System." Applied and Environmental Microbiology 71, no. 10 (October 2005): 6360–67. http://dx.doi.org/10.1128/aem.71.10.6360-6367.2005.
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ABSTRACT The decapeptide killer peptide (KP) derived from the sequence of a single-chain, anti-idiotypic antibody acting as a functional internal image of a microbicidal, broad-spectrum yeast killer toxin (KT) was shown to exert a strong microbicidal activity against human pathogens. With the aim to exploit this peptide to confer resistance to plant pathogens, we assayed its antimicrobial activity against a broad spectrum of phytopathogenic bacteria and fungi. Synthetic KP exhibited antimicrobial activity in vitro towards Pseudomonas syringae, Erwinia carotovora, Botrytis cinerea, and Fusarium oxysporum. KP was also expressed in plants by using a Potato virus X (PVX)-derived vector as a fusion to the viral coat protein, yielding chimeric virus particles (CVPs) displaying the heterologous peptide. Purified CVPs showed enhanced antimicrobial activity against the above-mentioned plant pathogens and human pathogens such as Staphylococcus aureus and Candida albicans. Moreover, in vivo assays designed to challenge KP-expressing plants (as CVPs) with Pseudomonas syringae pv. tabaci showed enhanced resistance to bacterial attack. The results indicate that the PVX-based display system is a high-yield, rapid, and efficient method to produce and evaluate antimicrobial peptides in plants, representing a milestone for the large-scale production of high-added-value peptides through molecular farming. Moreover, KP is a promising molecule to be stably engineered in plants to confer broad-spectrum resistance to phytopathogens.
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Ng, Charmaine, and Karina Yew-Hoong Gin. "Monitoring Antimicrobial Resistance Dissemination in Aquatic Systems." Water 11, no. 1 (January 3, 2019): 71. http://dx.doi.org/10.3390/w11010071.
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This special issue on Antimicrobial Resistance in Environmental Waters features 11 articles on monitoring and surveillance of antimicrobial resistance (AMR) in natural aquatic systems (reservoirs, rivers), and effluent discharge from water treatment plants to assess the effectiveness of AMR removal and resulting loads in treated waters. The occurrence and distribution of antimicrobials, antibiotic resistant bacteria (ARB), antibiotic resistance genes (ARGs) and mobile genetic elements (MGEs) was determined by utilizing a variety of techniques including liquid chromatography—mass spectrometry in tandem (LC-MS/MS), traditional culturing, antibiotic susceptibility testing (AST), molecular and OMIC approaches. Some of the key elements of AMR studies presented in this special issue highlight the underlying drivers of AMR contamination in the environment and evaluation of the hazard imposed on aquatic organisms in receiving environments through ecological risk assessments. As described in this issue, screening antimicrobial peptide (AMP) libraries for biofilm disruption and antimicrobial candidates are promising avenues for the development of new treatment options to eradicate resistance. This editorial puts into perspective the current AMR problem in the environment and potential new methods which could be applied to surveillance and monitoring efforts.
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Mishra, Biswajit, Jayaram Lakshmaiah Narayana, Tamara Lushnikova, Yingxia Zhang, Radha M. Golla, D. Zarena, and Guangshun Wang. "Sequence Permutation Generates Peptides with Different Antimicrobial and Antibiofilm Activities." Pharmaceuticals 13, no. 10 (September 25, 2020): 271. http://dx.doi.org/10.3390/ph13100271.
Full textAbstract:
Antibiotic resistance poses a threat to our society, and 10 million people could die by 2050. To design potent antimicrobials, we made use of the antimicrobial peptide database (APD). Using the database filtering technology, we identified a useful template and converted it into an effective peptide WW291 against methicillin-resistant Staphylococcus aureus (MRSA). Here, we compared the antibacterial activity and cytotoxicity of a family of peptides obtained from sequence permutation of WW291. The resulting eight WW peptides (WW291-WW298) gained different activities against a panel of bacteria. While WW295 inhibited the growth of Escherichia coli, WW298 was highly active against S. aureus USA300 LAC. Consistently with this, WW298 was more effective in permeating or depolarizing the S. aureus membranes, whereas WW295 potently permeated the E. coli membranes. In addition, WW298, but not WW295, inhibited the MRSA attachment and could disrupt its preformed biofilms more effectively than daptomycin. WW298 also protected wax moths Galleria mellonella from MRSA infection causing death. Thus, sequence permutation provides one useful avenue to generating antimicrobial peptides with varying activity spectra. Taken together with amino acid composition modulation, these methods may lead to narrow-spectrum peptides that are more promising to selectively eliminate invading pathogens without damaging commensal microbiota.