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

Objectives: To assess the efficacy of aztreonam-avibactam-auranofin (ATM-AVI-AUR) against a collection of 88 carbapenemase-producing Enterobacterales (CPE) clinical isolates and 6 in vitro selected ATM-AVI-resistant CPE with CMY-16 Tyr150Ser and Asn346His mutants or transformants. Methods: MICs of imipenem, ceftazidime-avibact8am (CAZ-AVI), ATM-AVI, CAZ-AVI-AUR and ATM-AVI-AUR were determined via the broth microdilution method. Genetic background and carbapenemase genes were determined by PCR and Sanger sequencing. Results: 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 MIC₅₀ (0.5 to 0.0625 μg/mL) and a 2-folding dilutions MIC reduction of MIC₉₀ (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 MIC₅₀ and MIC₉₀ 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 MIC₅₀ (0.0625 μg/mL) and MIC₉₀ (0.125 μg/mL) among single KPC-producers. Interestingly, the addition of AUR restored the ATM-AVI susceptibility against the 6 in vitro selected ATM-AVI-resistant CMY-16 Tyr150Ser and Asn346His mutants or transfromants, with the MICs reduced from ≥32 μg/mL (32->256 μg/mL) to ≤8 μg/mL (0.0625-8 μg/mL). Conclusions: Our results demonstrated that AUR potentiated the activities of CAZ-AVI and ATM-AVI against MBL-producing isolates in vitro. 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 Enterobacterales.