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A Strong Synergy Between the Thiopeptide Bacteriocin Micrococcin P1 and Rifampicin Against MRSA in a Murine Skin Infection Model.

ABSTRACT: Antibiotic-resistant bacterial pathogens have become a serious threat worldwide. One of these pathogens is methicillin-resistant Staphylococcus aureus (MRSA), a major cause of skin and soft tissue infections. In this study we identified a strain of Staphylococcus equorum producing a substance with high antimicrobial activity against many Gram-positive bacteria, including MRSA. By mass spectrometry and whole genome sequencing the antimicrobial substance was identified as the thiopeptide bacteriocin micrococcin P1 (MP1). Based on its properties we developed a one-step purification protocol resulting in high yield (15 mg/L) and high purity (98%) of MP1. For shorter incubation times (5-7 h) MP1 was very potent against MRSA but the inhibitory effect was overshadowed by resistance development during longer incubation time (24h or more). To overcome this problem a synergy study was performed with a number of commercially available antibiotics. Among the antibiotics tested, the combination of MP1 and rifampicin gave the best synergistic effect, with MIC values 25 and 60 times lower than for the individual drugs, respectively. To assess the therapeutic potential of the MP1-rifampicin combination, we used a murine skin infection model based on the use of the multidrug-resistant luciferase-tagged MRSA strain Xen31. As expected, neither of the single antimicrobials (MP1 or rifampicin) could eradicate Xen31 from the wounds. By contrary, the MP1-rifampicin combination was efficient not only to eradicate but also to prevent the recurrence of Xen31 infection. Furthermore, compared to fucidin cream, which is commonly used in skin infection treatments, MP1-rifampicin combination was superior in terms of preventing resistance development. Our results show that combining MP1, and probably other thiopeptides, with antibiotics can be a promising strategy to treat SSTIs caused by MRSA and likely many other Gram-positive bacteria.

SUBMITTER: Ovchinnikov KV

PROVIDER: S-EPMC8284338 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Staphylococcus aureus is a pathogen commonly found in nosocomial environments where infections can easily spread - especially given the reduced immune response of patients and large overlap between personnel in charge of their care. Although antibiotics are available to treat nosocomial infections, the increased occurrence of antibiotic resistance has rendered many treatments ineffective. Such is the case for methicillin resistant S. aureus (MRSA), which has continued to be a threat to public health since its emergence. For this reason, alternative treatment technologies utilizing antimicrobials such as bacteriocins, bacteriophages (phages) and phage endolysins are being developed. These antimicrobials provide an advantage over antibiotics in that many have narrow inhibition spectra, enabling treatments to be selected based on the target (pathogenic) bacterium while allowing for survival of commensal bacteria and thus avoiding collateral damage to the microbiome. Bacterial resistance to these treatments occurs less frequently than with antibiotics, particularly in circumstances where combinatory antimicrobial therapies are used. Phage therapy has been well established in Eastern Europe as an effective treatment against bacterial infections. While there are no Randomized Clinical Trials (RCTs) to our knowledge examining phage treatment of S. aureus infections that have completed all trial phases, numerous clinical trials are underway, and several commercial phage preparations are currently available to treat S. aureus infections. Bacteriocins have primarily been used in the food industry for bio-preservation applications. However, the idea of repurposing bacteriocins for human health is an attractive one considering their efficacy against many bacterial pathogens. There are concerns about the ability of bacteriocins to survive the gastrointestinal tract given their proteinaceous nature, however, this obstacle may be overcome by altering the administration route of the therapy through encapsulation, or by bioengineering protease-resistant variants. Obstacles such as enzymatic digestion are less of an issue for topical/local administration, for example, application to the surface of the skin. Bacteriocins have also shown impressive synergistic effects when used in conjunction with other antimicrobials, including antibiotics, which may allow antibiotic-based therapies to be used more sparingly with less resistance development. This review provides an updated account of known bacteriocins, phages and phage endolysins which have demonstrated an impressive ability to kill S. aureus strains. In particular, examples of antimicrobials with the ability to target MRSA strains and their subsequent use in a clinical setting are outlined.

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A Strong Synergy Between the Thiopeptide Bacteriocin Micrococcin P1 and Rifampicin Against MRSA in a Murine Skin Infection Model.

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