AUTHOR=Wang Wen , Huang Shifeng , Zou Chunhong , Ding Yanhui , Wang Huijuan , Pu Shuli , Liao Yunfeng , Du Hong , Wang Deqiang , Chen Liang , Niu Siqiang 

TITLE=In Vitro Activity of Auranofin in Combination With Aztreonam-Avibactam Against Metallo-β-lactamase (MBL)-Producing Enterobacterales

JOURNAL=Frontiers in Cellular and Infection Microbiology

VOLUME=11

YEAR=2021

URL=https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2021.755763

DOI=10.3389/fcimb.2021.755763

ISSN=2235-2988

ABSTRACT=<sec><title>Objectives</title><p>To assess the efficacy of aztreonam-avibactam-auranofin (ATM-AVI-AUR) against a collection of 88 carbapenemase-producing <italic>Enterobacterales</italic> (CPE) clinical isolates and 6 <italic>in vitro</italic> selected ATM-AVI-resistant CPE with CMY-16 Tyr150Ser and Asn346His mutants or transformants.</p></sec><sec><title>Methods</title><p>MICs of imipenem, ceftazidime-avibact8am (CAZ-AVI), ATM-AVI, CAZ-AVI-AUR and ATM-AVI-AUR were determined <italic>via</italic> the broth microdilution method. Genetic background and carbapenemase genes were determined by PCR and Sanger sequencing.</p></sec><sec><title>Results</title><p>AUR alone showed little antibacterial activity with AUR MICs were greater than 64 μg/mL for all the 88 clinical CPE isolates. The addition of AUR (16 μg/mL) resulted in an 3-folding dilutions MIC reduction of ATM-AVI MIC<sub>50</sub> (0.5 to 0.0625 μg/mL) and a 2-folding dilutions MIC reduction of MIC<sub>90</sub> (1 to 0.25 μg/mL) against all 88 clinical CPE isolates, respectively. Notably, the reduced ATM-AVI MIC values were mainly found in MBL-producers, and the MIC<sub>50</sub> and MIC<sub>90</sub> reduced by 2-folding dilutions (0.25 to 0.0625 μg/mL) and 3-folding dilutions (2 to 0.25 μg/mL) respectively by AUR among the 51 MBL-producers. By contrast, the addition of AUR did not showed significant effects on ATM-AVI MIC<sub>50</sub> (0.0625 μg/mL) and MIC<sub>90</sub> (0.125 μg/mL) among single KPC-producers. Interestingly, the addition of AUR restored the ATM-AVI susceptibility against the 6 <italic>in vitro</italic> selected ATM-AVI-resistant CMY-16 Tyr150Ser and Asn346His mutants or transfromants, with the MICs reduced from ≥32 μg/mL (32-&gt;256 μg/mL) to ≤8 μg/mL (0.0625-8 μg/mL).</p></sec><sec><title>Conclusions</title><p>Our results demonstrated that AUR potentiated the activities of CAZ-AVI and ATM-AVI against MBL-producing isolates <italic>in vitro</italic>. Importantly, AUR restored the ATM-AVI activity against ATM-AVI resistant mutant strains. As a clinically approved drug, AUR might be repurposed in combination with ATM-AVI to treat infections caused by highly resistant MBL-producing <italic>Enterobacterales.</italic></p></sec>