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Microbicidal effects of ?- and ?-defensins against antibiotic-resistant Staphylococcus aureus and Pseudomonas aeruginosa.

ABSTRACT: Antibiotic-resistant bacterial pathogens threaten public health. Because many antibiotics target specific bacterial enzymes or reactions, corresponding genes may mutate under selection and lead to antibiotic resistance. Accordingly, antimicrobials that selectively target overall microbial cell integrity may offer alternative approaches to therapeutic design. Naturally occurring mammalian ?- and ?-defensins are potent, non-toxic microbicides that may be useful for treating infections by antibiotic-resistant pathogens because certain defensin peptides disrupt bacterial, but not mammalian, cell membranes. To test this concept, clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA), including vancomycin heteroresistant strains, and ciprofloxacin-resistant Pseudomonas aeruginosa (Cip(R)-PA) were tested for sensitivity to ?-defensins Crp-4, RMAD-4 and HNPs 1-3, and to RTD-1, macaque ?-defensin-1. In vitro, 3??M Crp-4, RMAD-4 and RTD-1 reduced MRSA cell survival by 99%, regardless of vancomycin susceptibility. For PA clinical isolates that differ in fluoroquinolone resistance and virulence phenotype, peptide efficacy was independent of strain ciprofloxacin resistance, site of isolation or virulence factor expression. Thus, Crp-4, RMAD-4 and RTD-1 are effective in vitro antimicrobials against clinical isolates of MRSA and Cip(R)-PA, perhaps providing templates for development of ?- and ?-defensin-based microbicides against antibiotic resistant or virulent infectious agents.

SUBMITTER: Tai KP

PROVIDER: S-EPMC4062604 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Project description:Bald's eyesalve is an Anglo-Saxon medicinal remedy that has been used through ancient times to treat eye sty infections and may represent a source of ancientbiotics. This study assessed the efficacy of Bald's eyesalve against several strains of Staphylococcus aureus and Pseudomonas aeruginosa, including a multi-drug resistant phenotype, and identified the principal compound conveying antibacterial activity. Bald's eyesalve formulations were produced by combining garlic, onion or leek, wine, bovine bile, and brass, with specific ingredient omissions in several formulations, followed by incubation at 4 °C for 9 days. Bald's eyesalve formulation ES-GBBr exhibited the greatest antibacterial activity against S. aureus and P. aeruginosa. Fractionation of ES-GBBr using molecular size exclusion and organic solvent partitioning isolated its antibacterial activity to the small molecule nonpolar fraction, and 1D 1H NMR revealed the identity of the antibacterial agent to be allicin. Depletion of allicin from this fraction by addition of exogenous cysteine established that all observable growth inhibition originated from allicin. Quantification of allicin demonstrated that its concentration was significantly greater in ES-GBBr compared to the ES-O formulation; however, this was not due to greater yield. The antibacterial activity of allicin against S. aureus was antagonized by other ingredients within Bald's eyesalve, whereas they were additive or synergistic against P. aeruginosa. These results suggest that neither leek nor onion is necessary for the antibacterial efficacy of Bald's eyesalve against S. aureus or P. aeruginosa, and while allicin was identified as the principal antibacterial agent present, its activity is influenced differentially in the presence of additional Bald's eyesalve ingredients when used against S. aureus compared to P. aeruginosa. Ancientbiotics may provide a source of promising antibacterials; however, identifying the source of activity and assessing distinct formulations for cooperative effects are essential to using ancient remedies, such as Bald's eyesalve, effectively against drug resistant pathogens.

Project description:The recent emergence of antibiotic-resistant bacteria requires the development of new antibiotics or new agents capable of enhancing antibiotic activity. This study evaluated the antibacterial activity of lysozyme-chitosan oligosaccharide conjugates (LYZOX) against Pseudomonas aeruginosa, Acinetobacter baumannii and methicillin-resistant Staphylococcus aureus (MRSA), which should resolve the problem of antibiotic-resistant bacteria. Bactericidal tests showed that LYZOX killed 50% more P. aeruginosa (NBRC 13275), A. baumannii and MRSA than the control treatment after 60 min. In addition, LYZOX was shown to inhibit the growth of P. aeruginosa (NBRC 13275 and PAO1), A. baumannii and MRSA better than its components. To elucidate the antibacterial mechanism of LYZOX, we performed cell membrane integrity assays, N-phenyl-1-naphthylamine assays, 2-nitrophenyl β-D-galactopyranoside assays and confocal laser scanning microscopy. These results showed that LYZOX affected bacterial cell walls and increased the permeability of the outer membrane and the plasma membrane. Furthermore, each type of bacteria treated with LYZOX was observed by electron microscopy. Electron micrographs revealed that these bacteria had the morphological features of both lysozyme-treated and chitosan oligosaccharide-treated bacteria and that LYZOX destroyed bacterial cell walls, which caused the release of intracellular contents from cells. An acquired drug resistance test revealed that these bacteria were not able to acquire resistance to LYZOX. The hemolytic toxicity test demonstrated the low hemolytic activity of LYZOX. In conclusion, LYZOX exhibited antibacterial activity and low drug resistance in the presence of P. aeruginosa, A. baumannii and MRSA and showed low hemolytic toxicity. LYZOX affected bacterial membranes, leading to membrane disruption and the release of intracellular contents and consequent bacterial cell death. LYZOX may serve as a novel candidate drug that could be used for the control of refractory infections.

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Microbicidal effects of ?- and ?-defensins against antibiotic-resistant Staphylococcus aureus and Pseudomonas aeruginosa.

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