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- Title
A lipoglycopeptide antibiotic for Gram-positive biofilm-related infections.
- Authors
Blaskovich, Mark A. T.; Hansford, Karl A.; Butler, Mark S.; Ramu, Soumya; Kavanagh, Angela M.; Jarrad, Angie M.; Prasetyoputri, Anggia; Pitt, Miranda E.; Huang, Johnny X.; Lindahl, Fredrik; Ziora, Zyta M.; Bradford, Tanya; Muldoon, Craig; Rajaratnam, Premraj; Pelingon, Ruby; Edwards, David J.; Zhang, Bing; Amado, Maite; Elliott, Alysha G.; Zuegg, Johannes
- Abstract
Drug-resistant Gram-positive bacterial infections are still a substantial burden on the public health system, with two bacteria (Staphylococcus aureus and Streptococcus pneumoniae) accounting for over 1.5 million drug-resistant infections in the United States alone in 2017. In 2019, 250,000 deaths were attributed to these pathogens globally. We have developed a preclinical glycopeptide antibiotic, MCC5145, that has excellent potency (MIC90 ≤ 0.06 μg/ml) against hundreds of isolates of methicillin-resistant S. aureus (MRSA) and other Gram-positive bacteria, with a greater than 1000-fold margin over mammalian cell cytotoxicity values. The antibiotic has therapeutic in vivo efficacy when dosed subcutaneously in multiple murine models of established bacterial infections, including thigh infection with MRSA and blood septicemia with S. pneumoniae, as well as when dosed orally in an antibiotic-induced Clostridioides difficile infection model. MCC5145 exhibited reduced nephrotoxicity at microbiologically active doses in mice compared to vancomycin. MCC5145 also showed improved activity against biofilms compared to vancomycin, both in vitro and in vivo, and a low propensity to select for drug resistance. Characterization of drug action using a transposon library bioinformatic platform showed a mechanistic distinction from other glycopeptide antibiotics. Busting biofilms: Drug-resistant Gram-positive bacterial infections remain a critical concern, and new treatment modalities against them are needed in the clinic. Blaskovich et al. optimized a vancomycin-derived antibiotic bearing a membrane-targeting glycopeptide and demonstrated that this compound was effective in multiple mouse models of Gram-positive infections, including difficult-to-treat biofilms. The optimized compound was more potent than its parent, vancomycin, and had a low rate of resistance, suggesting that this candidate compound may warrant further development.
- Subjects
UNITED States; ANTIBIOTICS; GRAM-positive bacterial infections; GLYCOPEPTIDE antibiotics; GRAM-positive bacteria; CLOSTRIDIOIDES difficile; BIOFILMS; BACTERIAL diseases
- Publication
Science Translational Medicine, 2022, Vol 14, Issue 662, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.abj2381