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A lipoglycopeptide antibiotic for Gram-positive biofilm-related infections

Mark A T Blaskovich1, Karl A Hansford1, Mark S Butler1

  • 1Centre for Superbug Solutions, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland 4072, Australia.

Science Translational Medicine
|September 14, 2022
PubMed

Insights

A new glycopeptide antibiotic, MCC5145, shows high potency against drug-resistant Gram-positive bacteria like MRSA. It demonstrates therapeutic efficacy in vivo with reduced toxicity and improved biofilm activity compared to vancomycin.

Area of Science:

  • Microbiology
  • Infectious Diseases
  • Pharmacology

Background:

  • Drug-resistant Gram-positive bacterial infections pose a significant public health threat, causing millions of infections and hundreds of thousands of deaths globally.
  • Key pathogens include methicillin-resistant Staphylococcus aureus (MRSA) and Streptococcus pneumoniae, necessitating novel therapeutic strategies.
  • Existing treatments face challenges with efficacy, toxicity, and the emergence of resistance.

Purpose of the Study:

  • To evaluate the preclinical efficacy and safety of a novel glycopeptide antibiotic, MCC5145.
  • To compare MCC5145 with vancomycin regarding potency, toxicity, biofilm activity, and resistance development.
  • To elucidate the mechanism of action of MCC5145.

Main Methods:

  • In vitro susceptibility testing against Gram-positive bacteria, including MRSA isolates.
  • In vivo efficacy studies in murine models of MRSA thigh infection, S. pneumoniae septicemia, and Clostridioides difficile infection.
  • Assessment of nephrotoxicity and cytotoxicity in preclinical models.
  • In vitro and in vivo evaluation of antibiofilm activity.
  • Analysis of resistance selection propensity and mechanism of action using transposon sequencing.

Main Results:

  • MCC5145 demonstrated potent activity (MIC90 ≤ 0.06 μg/ml) against Gram-positive bacteria, including MRSA.
  • The antibiotic exhibited therapeutic efficacy in multiple murine infection models via subcutaneous and oral administration.
  • MCC5145 showed a >1000-fold margin over mammalian cell cytotoxicity and reduced nephrotoxicity compared to vancomycin.
  • Enhanced in vitro and in vivo activity against biofilms and a low propensity for resistance selection were observed.
  • Mechanistic studies indicated MCC5145 is distinct from other glycopeptide antibiotics.

Conclusions:

  • MCC5145 is a promising preclinical glycopeptide antibiotic with potent activity against drug-resistant Gram-positive pathogens.
  • Its favorable safety profile, including reduced nephrotoxicity, and improved antibiofilm efficacy offer advantages over vancomycin.
  • MCC5145 represents a potential new therapeutic option for challenging bacterial infections with a distinct mechanism of action.

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