In Vitro Antibacterial Activity And In Vivo Efficacy Of Sulbactam-Durlobactam Against Pathogenic Burkholderia Species

The Gram-negative bacterial genus Burkholderia includes several hard-to-treat human pathogens: two biothreat species, Burkholderia mallei (causing glanders) and B. pseudomallei (causing melioidosis), and the B. cepacia complex (BCC) and B. gladioli, which cause chronic lung infections in persons with cystic fibrosis. All Burkholderia spp. possess an Ambler class A Pen beta-lactamase, which confers resistance to beta-lactams. The beta-lactam-beta-lactamase inhibitor combination sulbactam-durlobactam (SUL-DUR) is in clinical development for the treatment of Acinetobacter infections. In this study, we evaluated SUL-DUR for in vitro and in vivo activity against Burkholderia clinical isolates. We measured MICs of SUL-DUR against BCC and B. gladioli (n =150), B. mallei (n = 30), and B. pseudomallei (n = 28), studied the kinetics of inhibition of the PenA1 beta-lactamase from B. multivorans and the Penl beta-lactamase from B. pseudomallei by durlobactam, tested for bla(PenA1) induction by SUL-DUR, and evaluated in vivo efficacy in a mouse model of melioidosis. SUL-DUR inhibited growth of 873% of the BCC and B. gladioli strains and 100% of the B. mallei and B. pseudomallei strains at 4/4 mu g/ml. Durlobactam potently inhibited PenA1 and Penl with second-order rate constant for inactivation (K-2/K) values of 3.9 x 10(6) M-1 s(-1) and 2.6 x 10(3) M-1 s(-1) and apparent K-i (K-iapp) 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 vivo in a murine melioidosis model. Taken together, these data suggest that SUL-DUR may be useful as a treatment for Burkholderia infections.