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Efficacy of aspergillomarasmine A/meropenem combinations with and without avibactam against bacterial strains producing multiple ß-lactamases.
Rotondo, Caitlyn M; Wright, Gerard D.
Afiliação
  • Rotondo CM; David Braley Centre for Antibiotic Discovery, McMaster University, Hamilton, Ontario, Canada.
  • Wright GD; M.G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.
Antimicrob Agents Chemother ; 68(9): e0027224, 2024 Sep 04.
Article em En | MEDLINE | ID: mdl-39133022
ABSTRACT
The effectiveness of ß-lactam antibiotics is increasingly threatened by resistant bacteria that harbor hydrolytic ß-lactamase enzymes. Depending on the class of ß-lactamase present, ß-lactam hydrolysis can occur through one of two general molecular mechanisms. Metallo-ß-lactamases (MBLs) require active site Zn2+ ions, whereas serine-ß-lactamases (SBLs) deploy a catalytic serine residue. The result in both cases is drug inactivation via the opening of the ß-lactam warhead of the antibiotic. MBLs confer resistance to most ß-lactams and are non-susceptible to SBL inhibitors, including recently approved diazabicyclooctanes, such as avibactam; consequently, these enzymes represent a growing threat to public health. Aspergillomarasmine A (AMA), a fungal natural product, can rescue the activity of the ß-lactam antibiotic meropenem against MBL-expressing bacterial strains. However, the effectiveness of this ß-lactam/ß-lactamase inhibitor combination against bacteria producing multiple ß-lactamases remains unknown. We systematically investigated the efficacy of AMA/meropenem combination therapy with and without avibactam against 10 Escherichia coli and 10 Klebsiella pneumoniae laboratory strains tandemly expressing single MBL and SBL enzymes. Cell-based assays demonstrated that laboratory strains producing NDM-1 and KPC-2 carbapenemases were resistant to the AMA/meropenem combination but became drug-susceptible upon adding avibactam. We also probed these combinations against 30 clinical isolates expressing multiple ß-lactamases. E. coli, Enterobacter cloacae, and K. pneumoniae clinical isolates were more susceptible to AMA, avibactam, and meropenem than Pseudomonas aeruginosa and Acinetobacter baumannii isolates. Overall, the results demonstrate that a triple combination of AMA/avibactam/meropenem has potential for empirical treatment of infections caused by multiple ß-lactamase-producing bacteria, especially Enterobacterales.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Beta-Lactamases / Testes de Sensibilidade Microbiana / Escherichia coli / Compostos Azabicíclicos / Meropeném / Antibacterianos Limite: Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Beta-Lactamases / Testes de Sensibilidade Microbiana / Escherichia coli / Compostos Azabicíclicos / Meropeném / Antibacterianos Limite: Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article