AAI101, a Novel β-Lactamase Inhibitor: Microbiological and Enzymatic Profiling

BACKGROUND: AAI101 is a novel β-lactamase inhibitor (BLI), active against ESBLs and other β-lactamases. AAI101 combined with cefepime (FEP) is in Phase 2 clinical trials. The objective of this study was to determine differences between AAI101 and tazobactam in their inhibition of selected β-lactamases of clinical relevance. METHODS: Isogenic E. coli strains expressing single clinically relevant β-lactamases were tested for susceptibility (broth microdilution MIC) to FEP, FEP/AAI101 and piperacillin-tazobactam (P/T). Periplasmic β-lactamase extracts from selected strains then were used to determine IC(50)s for AAI101 and for tazobactam. β-Lactamases with low IC(50)s for AAI101 were purified, and steady-state inactivation kinetics determined for AAI101 and for tazobactam. RESULTS: AAI101 restored activity of FEP against E. coli strains producing defined β-lactamases, and FEP/AAI101 was more potent than P/T (Table). CONCLUSION: Addition of AAI101 enhances cefepime activity vs. a selected array of β-lactamases expressed in E. coli in an isogenic Background. The inhibitory kinetics of β-lactamases by AAI101 compared with those of tazobactam indicate different mechanisms of β-lactamase inhibition. DISCLOSURES: K. M. Papp-Wallace, Entasis: Grant Investigator, Research grant Allecra: Grant Investigator, Research grant Merck: Grant Investigator, Research grant; Roche: Grant Investigator, Research grant Allergan: Grant Investigator, Research grant M. R. Jacobs, Allecra: Grant Investigator, Research grant Roche: Grant Investigator, Research grant Shionogi: Grant Investigator, Research grant; R. A. Bonomo, Entasis: Grant Investigator, Research grant Allecra: Grant Investigator, Research grant Wockhardt: Grant Investigator, Research grant Merck: Grant Investigator, Research grant Roche: Grant Investigator, Research grant GSK: Grant Investigator, Research grant Allergan: Grant Investigator, Research grant Shionogi: Grant Investigator, Research grant