A lipoglycopeptide antibiotic for Gram-positive biofilm-related infections

Article


Blaskovich, Mark A. T., Hansford, Karl A., Butler, Mark S., Ramu, Soumya, Kavanagh, Angela M., Jarrad, Angie M., Prasetyoputri, Anggia, Pitt, Miranda 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., ..., Cooper M.A.. 2022. "A lipoglycopeptide antibiotic for Gram-positive biofilm-related infections." Science Translational Medicine. 14 (662), pp. 1-16. https://doi.org/10.1126/scitranslmed.abj2381
Article Title

A lipoglycopeptide antibiotic for Gram-positive biofilm-related infections

ERA Journal ID123655
Article CategoryArticle
AuthorsBlaskovich, Mark A. T., Hansford, Karl A., Butler, Mark S., Ramu, Soumya, Kavanagh, Angela M., Jarrad, Angie M., Prasetyoputri, Anggia, Pitt, Miranda 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., Coin L., Woischnig A.K., Khanna N., Breidenstein E., Stincone A., Mason C., Khan N., Cho H.K., Karau M.J., Greenwood-Quaintance K.E., Patel R., Wootton M., James M.L., Hutton M.L., Lyras D., Ogunniyi A.D., Mahdi, L. K., Trott D.J., Wu X., Niles S., Lewis K., Smith J.R., Barber K.E., Yim J., Rice S.A., Rybak M.J., Ishmael C.R., Hori K.R., Bernthal N.M., Francis K.P., Roberts J.A., Paterson D.L. and Cooper M.A.
Journal TitleScience Translational Medicine
Journal Citation14 (662), pp. 1-16
Article Numberabj2381
Number of Pages16
Year2022
Place of PublicationUnited States
ISSN1946-6234
1946-6242
Digital Object Identifier (DOI)https://doi.org/10.1126/scitranslmed.abj2381
Web Address (URL)https://www.science.org/doi/10.1126/scitranslmed.abj2381
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.

Byline AffiliationsUniversity of Queensland
University of Adelaide
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