Suppression of ?-Lactam Resistance by Aspergillomarasmine A Is Influenced by both the Metallo-?-Lactamase Target and the Antibiotic Partner.

ABSTRACT: The rise of Gram-negative pathogens expressing metallo-?-lactamases (MBLs) is a growing concern, threatening the efficacy of ?-lactam antibiotics, in particular, the carbapenems. There are no inhibitors of MBLs in current clinical use. Aspergillomarasmine A (AMA) is an MBL inhibitor isolated from Aspergillus versicolor with the ability to rescue meropenem activity in MBL-producing bacteria both in vitro and in vivo Here, we systematically explored the pairing of AMA with six ?-lactam antibiotic partners against 19 MBLs from three subclasses (B1, B2, and B3). Cell-based assays performed with Escherichia coli and Klebsiella pneumoniae showed that bacteria producing NDM-1 and VIM-2 of subclass B1 were the most susceptible to AMA inhibition, whereas bacteria producing CphA2 and AIM-1 of subclasses B2 and B3, respectively, were the least sensitive. Intracellular antibiotic accumulation assays and in vitro enzyme assays demonstrated that the efficacy of AMA/?-lactam combinations did not correlate with outer membrane permeability or drug efflux. We determined that the optimal ?-lactam partners for AMA are the carbapenem antibiotics and that the efficacy of AMA is linked to the Zn2+ affinity of specific MBLs.

SUBMITTER: Rotondo CM 

PROVIDER: S-EPMC7179287 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature