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Review
. 2021 Jul 19:12:709974.
doi: 10.3389/fmicb.2021.709974. eCollection 2021.

Durlobactam, a New Diazabicyclooctane β-Lactamase Inhibitor for the Treatment of Acinetobacter Infections in Combination With Sulbactam

Adam B Shapiro  1 , Samir H Moussa  1 , Sarah M McLeod  1 , Thomas Durand-Réville  1 , Alita A Miller  1
Affiliations
Review

Durlobactam, a New Diazabicyclooctane β-Lactamase Inhibitor for the Treatment of Acinetobacter Infections in Combination With Sulbactam

Adam B Shapiro et al. Front Microbiol. .

Abstract

Durlobactam is a new member of the diazabicyclooctane class of β-lactamase inhibitors with broad spectrum activity against Ambler class A, C, and D serine β-lactamases. Sulbactam is a first generation β-lactamase inhibitor with activity limited to a subset of class A enzymes that also has direct-acting antibacterial activity against Acinetobacter spp. The latter feature is due to sulbactam's ability to inhibit certain penicillin-binding proteins, essential enzymes involved in bacterial cell wall synthesis in this pathogen. Because sulbactam is also susceptible to cleavage by numerous β-lactamases, its clinical utility for the treatment of contemporary Acinetobacter infections is quite limited. However, when combined with durlobactam, the activity of sulbactam is effectively restored against these notoriously multidrug-resistant strains. This sulbactam-durlobactam combination is currently in late-stage development for the treatment of Acinectobacter infections, including those caused by carbapenem-resistant isolates, for which there is a high unmet medical need. The following mini-review summarizes the molecular drivers of efficacy of this combination against this troublesome pathogen, with an emphasis on the biochemical features of each partner.

Keywords: Acinetobacter; DBO; durlobactam; sulbactam; β-lactamase inhibitor.

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Conflict of interest statement

All co-authors are employees of Entasis Therapeutics. The authors declare that this study received funding from Entasis Therapeutics. The funder had the following involvement in the study: the study design, collection, analysis, interpretation of data, the writing of this article and the decision to submit it for publication.

Figures

FIGURE 1
FIGURE 1
Structural details for the mechanism of action of sulbactam-durlobactam. (A) Computational model of sulbactam bound to the active site of Acinetobacter baumannii PBP3 (PDB: 3UE3). Covalent docking was performed in ICM-Pro version 3.8 and structure visualized in UCSF Chimera version 1.15 (Pettersen et al., 2004), with sulbactam bound to the PBP3 active site serine, shown in green. Sulbactam-resistant mutations are indicated in red and sulbactam is shown in cyan. (B) Durlobactam bound to the active site of OXA24/40 (PDB: 6MPQ). The inhibitor is shown in blue carbon atom stick representation, whereas the protein is depicted in gray carbon stick representation. The K84 side chain was observed in two conformations: one carbamylated and one non-carbamylated [0.6 and 0.4 occupancy conformations labeled a and b, respectively]. A chloride ion with 0.4 occupancy was also refined in the active site (green sphere). Hydrogen bonds between durlobactam and OXA24/40 are shown with dashed lines. Water molecules are depicted as red spheres. Reproduced from Barnes et al. (2019) with permission from the authors.
SCHEME 1
SCHEME 1
Mechanism of action of durlobactam.
See this image and copyright information in PMC

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