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Random peptide mixtures entrapped within a copper-cuprite matrix: new antimicrobial agent against methicillin-resistant Staphylococcus aureus.

ABSTRACT: The emergence of global antibiotic resistance necessitates the urgent need to develop new and effective antimicrobial agents. Combination of two antimicrobial agents can potentially improve antimicrobial potency and mitigate the development of resistance. Therefore, we have utilized metal molecular doping methodology whereby antimicrobial random peptides mixture (RPMs) are entrapped in a bactericidal copper metal matrix. The copper/RPM composite exhibits greater antimicrobial activity toward methicillin-resistant Staphylococcus aureus (MRSA) than either copper or RPMs alone. Our findings indicate that this bactericidal antimicrobial biomaterial could be utilized to efficiently eradicate antibiotic-resistant pathogenic bacteria for health, agricultural and environmental applications.

SUBMITTER: Bauer TS

PROVIDER: S-EPMC6677760 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Random peptide mixtures entrapped within a copper-cuprite matrix: new antimicrobial agent against methicillin-resistant Staphylococcus aureus.

Bauer Tal Stern TS Menagen Barak B Avnir David D Hayouka Zvi Z

Scientific reports 20190802 1

The emergence of global antibiotic resistance necessitates the urgent need to develop new and effective antimicrobial agents. Combination of two antimicrobial agents can potentially improve antimicrobial potency and mitigate the development of resistance. Therefore, we have utilized metal molecular doping methodology whereby antimicrobial random peptides mixture (RPMs) are entrapped in a bactericidal copper metal matrix. The copper/RPM composite exhibits greater antimicrobial activity toward met ...[more]

PMID: 31375700

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Project description:The chemotherapeutic options for methicillin-resistant Staphylococcus aureus (MRSA) infections are limited. Due to the multiple resistant MRSA, therapeutic failure has occurred frequently, even using antibiotics belonging to different categories in clinical scenarios, very recently. This study aimed to investigate the interactions between 11 antibiotics representing different mechanisms of action against MRSA strains and provide therapeutic strategies for clinical infections. Susceptibilities for MRSA strains were determined by broth microdilution or agar dilution according to CLSI guideline. By grouping with each other, a total of 55 combinations were evaluated. The potential synergism was detected through drug interaction assays and further investigated for time-killing curves and an in vivo neutropenic mouse infection model. A total of six combinations (vancomycin with rifampicin, vancomycin with oxacillin, levofloxacin with oxacillin, gentamycin with oxacillin, clindamycin with oxacillin, and clindamycin with levofloxacin) showed synergistic activity against the MRSA ATCC 43300 strain. However, antibacterial activity against clinical isolate #161402 was only observed when vancomycin combined with oxacillin or rifampicin in time-killing assays. Next, therapeutic effectiveness of vancomycin/oxacillin and vancomycin/rifampicin was verified by an in vivo mouse infection model inoculated with #161402. Further investigations on antimicrobial synergism of vancomycin plus oxacillin and vancomycin plus rifampicin against 113 wild-type MRSA strains were evidenced by combined antibiotic MICs and bacterial growth inhibition and in vitro dynamic killing profiles. In summary, vancomycin/rifampicin and vancomycin/oxacillin are the most potential combinations for clinical MRSA infection upon both in vitro and in vivo tests. Other synergetic combinations of levofloxacin/oxacillin, gentamycin/oxacillin, clindamycin/oxacillin, and clindamycin/fosfomycin are also selected but may need more assessment for further application.

Project description:Urinary tract infection (UTI) is one of the most common infectious conditions affecting people in the United States and around the world. Our knowledge of the host-pathogen interaction during UTI caused by Gram-positive bacterial uropathogens is limited compared to that for Gram-negative pathogens. Here, we investigated whether copper and the primary copper-containing protein, ceruloplasmin, are mobilized to urine during naturally occurring UTI caused by Gram-positive uropathogens in patients. Next, we probed the role of copper resistance in the fitness of methicillin-resistant Staphylococcus aureus (MRSA) during experimental UTI in a murine model. Our findings demonstrate that urinary copper and ceruloplasmin content are elevated during UTI caused by Enterococcus faecalis, S. aureus, S. epidermidis, and S. saprophyticus. MRSA strains successfully colonize the urinary tract of female CBA mice with selective induction of inflammation in the kidneys but not the bladder. MRSA mutants lacking CopL, a copper-binding cell surface lipoprotein, and the ACME genomic region containing copL, exhibit decreased fitness in the mouse urinary tract compared to parental strains. Copper sensitivity assays, cell-associated copper and iron content, and bioavailability of iron during copper stress demonstrate that homeostasis of copper and iron is interlinked in S. aureus. Importantly, relative fitness of the MRSA mutant lacking the ACME region is further decreased in mice that receive supplemental copper compared to the parental strain. In summary, copper is mobilized to the urinary tract during UTI caused by Gram-positive pathogens, and copper resistance is a fitness factor for MRSA during UTI. IMPORTANCE Urinary tract infection (UTI) is an extremely common infectious condition affecting people throughout the world. Increasing antibiotic resistance in pathogens causing UTI threatens our ability to continue to treat patients in the clinics. Better understanding of the host-pathogen interface is critical for development of novel interventional strategies. Here, we sought to elucidate the role of copper in host-Staphylococcus aureus interaction during UTI. Our results reveal that copper is mobilized to the urine as a host response in patients with UTI. Our findings from the murine model of UTI demonstrate that copper resistance is involved in the fitness of methicillin-resistant S. aureus (MRSA) during interaction with the host. We also establish a critical link between adaptation to copper stress and iron homeostasis in S. aureus.

Dataset Information

Random peptide mixtures entrapped within a copper-cuprite matrix: new antimicrobial agent against methicillin-resistant Staphylococcus aureus.

Publications

Random peptide mixtures entrapped within a copper-cuprite matrix: new antimicrobial agent against methicillin-resistant Staphylococcus aureus.

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