A lipoglycopeptide antibiotic for Gram-positive biofilm-related infections

Mark A.T. Blaskovich, Karl A. Hansford, Mark S. Butler, Soumya Ramu, Angela M. Kavanagh, Angie M. Jarrad, Anggia Prasetyoputri, Miranda E. Pitt, Johnny X. Huang, Fredrik Lindahl, Zyta M. Ziora, Tanya Bradford, Craig Muldoon, Premraj Rajaratnam, Ruby Pelingon, David J. Edwards, Bing Zhang, Maite Amado, Alysha G. Elliott, Johannes ZueggLachlan Coin, Anne Kathrin Woischnig, Nina Khanna, Elena Breidenstein, Anna Stincone, Clive Mason, Nawaz Khan, Hye Kyung Cho, Melissa J. Karau, Kerryl E. Greenwood-Quaintance, Robin Patel, Mandy Wootton, Meagan L. James, Melanie L. Hutton, Dena Lyras, Abiodun D. Ogunniyi, Layla K. Mahdi, Darren J. Trott, Xiaoqian Wu, Samantha Niles, Kim Lewis, Jordan R. Smith, Katie E. Barber, Juwon Yim, Seth Alan Rice, Michael J. Rybak, Chad R. Ishmael, Kellyn R. Hori, Nicholas M. Bernthal, Kevin P. Francis, Jason A. Roberts, David L. Paterson, Matthew A. Cooper

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Article numberabj2381
JournalScience translational medicine
Issue number662
StatePublished - Sep 14 2022

ASJC Scopus subject areas

  • General Medicine


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