Efficacy of aspergillomarasmine A/meropenem combinations with and without avibactam against bacterial strains producing multiple β-lactamases.

Autor:	Rotondo CM; David Braley Centre for Antibiotic Discovery, McMaster University, Hamilton, Ontario, Canada.; M.G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada., Wright GD; David Braley Centre for Antibiotic Discovery, McMaster University, Hamilton, Ontario, Canada.; M.G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
Jazyk:	angličtina
Zdroj:	Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2024 Sep 04; Vol. 68 (9), pp. e0027224. Date of Electronic Publication: 2024 Aug 12.
DOI:	10.1128/aac.00272-24
Abstrakt:	The effectiveness of β-lactam antibiotics is increasingly threatened by resistant bacteria that harbor hydrolytic β-lactamase enzymes. Depending on the class of β-lactamase present, β-lactam hydrolysis can occur through one of two general molecular mechanisms. Metallo-β-lactamases (MBLs) require active site Zn 2+ ions, whereas serine-β-lactamases (SBLs) deploy a catalytic serine residue. The result in both cases is drug inactivation via the opening of the β-lactam warhead of the antibiotic. MBLs confer resistance to most β-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 β-lactam antibiotic meropenem against MBL-expressing bacterial strains. However, the effectiveness of this β-lactam/β-lactamase inhibitor combination against bacteria producing multiple β-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 β-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 β-lactamase-producing bacteria, especially Enterobacterales. Competing Interests: The authors declare no conflict of interest.
Databáze:	MEDLINE
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