Antibacterial Activity andEfficacy of Sulbactam-Durlobactam against PathogenicSpecies.

Abstract

The Gram-negative bacterial genusincludes several hard-to-treat human pathogens: two biothreat species,(causing glanders) and(causing melioidosis), and thecomplex (BCC) and, which cause chronic lung infections in persons with cystic fibrosis. Allspp. 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 ofinfections. In this study, we evaluated SUL-DUR forandactivity againstclinical isolates. We measured MICs of SUL-DUR against BCC and( = 150),( = 30), and( = 28), studied the kinetics of inhibition of the PenA1 β-lactamase fromand the PenI β-lactamase fromby durlobactam, tested forinduction by SUL-DUR, and evaluatedefficacy in a mouse model of melioidosis. SUL-DUR inhibited growth of 87.3% of the BCC andstrains and 100% of theandstrains at 4/4 μg/ml. Durlobactam potently inhibited PenA1 and PenI with second-order rate constant for inactivation () values of 3.9 × 10Msand 2.6 × 10Msand 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 activityin a murine melioidosis model. Taken together, these data suggest that SUL-DUR may be useful as a treatment forinfections.