A lipoglycopeptide antibiotic for Gram-positive biofilm-related infections

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dc.contributor.authorBlaskovich, M.A.T.
dc.contributor.authorHansford, K.A.
dc.contributor.authorButler, M.S.
dc.contributor.authorRamu, S.
dc.contributor.authorKavanagh, A.M.
dc.contributor.authorJarrad, A.M.
dc.contributor.authorPrasetyoputri, A.
dc.contributor.authorPitt, M.E.
dc.contributor.authorHuang, J.X.
dc.contributor.authorLindahl, F.
dc.contributor.authorZiora, Z.M.
dc.contributor.authorBradford, T.
dc.contributor.authorMuldoon, C.
dc.contributor.authorRajaratnam, P.
dc.contributor.authorPelingon, R.
dc.contributor.authorEdwards, D.J.
dc.contributor.authorZhang, B.
dc.contributor.authorAmado, M.
dc.contributor.authorElliott, A.G.
dc.contributor.authorZuegg, J.
dc.contributor.authoret al.
dc.date.issued2022
dc.description.abstractDrug-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.
dc.description.statementofresponsibilityMark A. T. Blaskovich ... Abiodun D. Ogunniy ... Darren J. Trott ... et al.
dc.identifier.citationScience Translational Medicine, 2022; 14(662):1-16
dc.identifier.doi10.1126/scitranslmed.abj2381
dc.identifier.issn1946-6234
dc.identifier.issn1946-6242
dc.identifier.orcidJarrad, A.M. [0000-0001-9293-1758]
dc.identifier.orcidOgunniyi, A.D. [0000-0001-9308-5629]
dc.identifier.orcidTrott, D.J. [0000-0002-8297-5770]
dc.identifier.urihttps://hdl.handle.net/2440/137234
dc.language.isoen
dc.publisherAmerican Association for the Advancement of Science
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1059354
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/631632
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1026922
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1113719
dc.rights© 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works
dc.source.urihttps://doi.org/10.1126/scitranslmed.abj2381
dc.subjectAnimals
dc.subjectMammals
dc.subjectMice
dc.subjectBiofilms
dc.subjectStreptococcus pneumoniae
dc.subjectGram-Positive Bacterial Infections
dc.subjectGlycopeptides
dc.subjectVancomycin
dc.subjectAnti-Infective Agents
dc.subjectAnti-Bacterial Agents
dc.subjectMicrobial Sensitivity Tests
dc.subjectMethicillin-Resistant Staphylococcus aureus
dc.subjectLipoglycopeptides
dc.subject.meshAnimals
dc.subject.meshMammals
dc.subject.meshMice
dc.subject.meshBiofilms
dc.subject.meshStreptococcus pneumoniae
dc.subject.meshGram-Positive Bacterial Infections
dc.subject.meshGlycopeptides
dc.subject.meshVancomycin
dc.subject.meshAnti-Infective Agents
dc.subject.meshAnti-Bacterial Agents
dc.subject.meshMicrobial Sensitivity Tests
dc.subject.meshMethicillin-Resistant Staphylococcus aureus
dc.subject.meshLipoglycopeptides
dc.titleA lipoglycopeptide antibiotic for Gram-positive biofilm-related infections
dc.typeJournal article
pubs.publication-statusPublished

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