In Vitro Antibacterial Activity and In Vivo Efficacy of Sulbactam-Durlobactam against Pathogenic Burkholderia Species

Krisztina M Papp-Wallace; Adam B Shapiro; Scott A Becka; Elise T Zeiser; John J LiPuma; Douglas J Lane; Rekha G Panchal; John P Mueller; John P O'Donnell; Alita A Miller

doi:10.1128/AAC.01930-20

In Vitro Antibacterial Activity and In Vivo Efficacy of Sulbactam-Durlobactam against Pathogenic Burkholderia Species

Antimicrob Agents Chemother. 2021 Feb 17;65(3):e01930-20. doi: 10.1128/AAC.01930-20. Print 2021 Feb 17.

Authors

Krisztina M Papp-Wallace^{1

2

3}, Adam B Shapiro⁴, Scott A Becka¹, Elise T Zeiser¹, John J LiPuma⁵, Douglas J Lane⁶, Rekha G Panchal⁶, John P Mueller⁴, John P O'Donnell⁴, Alita A Miller⁷

Affiliations

¹ Research Service, VA Northeast Healthcare System, Cleveland, Ohio, USA.
² Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
³ Department of Biochemistry, Case Western Reserve University, Cleveland, Ohio, USA.
⁴ Entasis Therapeutics, Waltham, Massachusetts, USA.
⁵ Department of Pediatrics, University of Michigan Medical School, Ann Arbor, Michigan, USA.
⁶ Therapeutic Discovery Branch, U.S. Army Medical Research Institute of Infectious Diseases, Frederick, Maryland, USA.
⁷ Entasis Therapeutics, Waltham, Massachusetts, USA alita.miller@entasistx.com.

Abstract

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 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 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 β-lactamase from B. multivorans and the PenI β-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 87.3% of the BCC and B. gladioli strains and 100% of the B. mallei and B. pseudomallei strains at 4/4 μg/ml. Durlobactam potently inhibited PenA1 and PenI with second-order rate constant for inactivation (k₂/K) values of 3.9 × 10⁶ M^-1 s^-1 and 2.6 × 10³ M^-1 s^-1 and apparent K_i (K_i_app) 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.

Keywords: Burkholderia; beta-lactamase inhibitor; beta-lactamases; biothreat pathogen; cystic fibrosis; melioidosis.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Anti-Bacterial Agents / pharmacology
Burkholderia mallei*
Burkholderia pseudomallei*
Burkholderia*
Glanders* / drug therapy
Horses
Melioidosis* / drug therapy
Mice
Sulbactam / pharmacology

Substances

Anti-Bacterial Agents
Sulbactam

Grants and funding

I01 BX002872/BX/BLRD VA/United States