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Type: Journal article
Title: A lipoglycopeptide antibiotic for Gram-positive biofilm-related infections
Author: Blaskovich, M.A.T.
Hansford, K.A.
Butler, M.S.
Ramu, S.
Kavanagh, A.M.
Jarrad, A.M.
Prasetyoputri, A.
Pitt, M.E.
Huang, J.X.
Lindahl, F.
Ziora, Z.M.
Bradford, T.
Muldoon, C.
Rajaratnam, P.
Pelingon, R.
Edwards, D.J.
Zhang, B.
Amado, M.
Elliott, A.G.
Zuegg, J.
et al.
Citation: Science Translational Medicine, 2022; 14(662):1-16
Publisher: American Association for the Advancement of Science
Issue Date: 2022
ISSN: 1946-6234
Statement of
Mark A. T. Blaskovich ... Abiodun D. Ogunniy ... Darren J. Trott ... et al.
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 g/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 antibioticinduced 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.
Keywords: Animals
Streptococcus pneumoniae
Gram-Positive Bacterial Infections
Anti-Infective Agents
Anti-Bacterial Agents
Microbial Sensitivity Tests
Methicillin-Resistant Staphylococcus aureus
Rights: © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works
DOI: 10.1126/scitranslmed.abj2381
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Appears in Collections:Animal and Veterinary Sciences publications

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