Antibacterial Activity and Efficacy of Sulbactam-Durlobactam against Pathogenic Species.

The Gram-negative bacterial genus includes several hard-to-treat human pathogens: two biothreat species, (causing glanders) and (causing melioidosis), and the complex (BCC) and , which cause chronic lung infections in persons with cystic fibrosis. All spp. possess an Ambler class A Pen β-lactamase, which confers resistance to β-lactams. The β-lactam-β-lactamase inhibitor combination sulbactam-durlobactam (SUL-DUR) is in clinical development for the treatment of infections. In this study, we evaluated SUL-DUR for and activity against clinical isolates. We measured MICs of SUL-DUR against BCC and ( = 150), ( = 30), and ( = 28), studied the kinetics of inhibition of the PenA1 β-lactamase from and the PenI β-lactamase from by durlobactam, tested for induction by SUL-DUR, and evaluated efficacy in a mouse model of melioidosis. SUL-DUR inhibited growth of 87.3% of the BCC and strains and 100% of the and strains at 4/4 μg/ml. Durlobactam potently inhibited PenA1 and PenI with second-order rate constant for inactivation () values of 3.9 × 10 M s and 2.6 × 10 M s and apparent () of 15 nM and 241 nM, respectively, by forming highly stable covalent complexes. Neither sulbactam, durlobactam, nor SUL-DUR increased production of PenA1. SUL-DUR demonstrated activity in a murine melioidosis model. Taken together, these data suggest that SUL-DUR may be useful as a treatment for infections.