β-Lactamase Inhibition Strategies for Acinetobacter Infections

Acinetobacter species, and in particular Acinetobacter baumannii, have emerged as leading causes of hospital-acquired infections due to their remarkable ability to acquire and express diverse β-lactamases. These enzymes hydrolyse β-lactam antibiotics, including penicillins, cephalosporins and carbapenems, rendering standard treatments ineffective. In response, inhibitor-based strategies have evolved from early suicide inhibitors to next-generation non-β-lactam scaffolds that target a broader spectrum of serine β-lactamases, including Ambler classes A, C and D. Central to this approach is the use of diazabicyclooctane and diazabicyclononane chemotypes that form stable adducts with active-site serine residues, protecting companion β-lactams from enzymatic degradation. Combinations such as sulbactam with novel inhibitors restore both inhibitor activity and direct antibacterial effects by simultaneously blocking penicillin-binding proteins and β-lactamases. Beyond chemical innovation, surveillance and structural studies have identified emerging resistance mechanisms—metallo-β-lactamases, target-site mutations and efflux pump overexpression—that guide optimisation of inhibitor potency, dosing regimens and partner drug selection. Together, these advances underpin a pipeline of targeted therapies poised to address multidrug-resistant Acinetobacter infections on a global scale.

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β-Lactamase Inhibition Strategies for Acinetobacter Infections publication trend

The graph below shows the total number of articles in β-lactamase inhibition strategies for acinetobacter infections across all publications each year (not limited to Nature Index journals).

Technical terms

β-lactamase: Enzyme produced by bacteria that hydrolyses the β-lactam ring of antibiotics, deactivating their antimicrobial activity.

β-lactamase inhibitor: Compound that binds to and inactivates β-lactamase enzymes, often restoring the efficacy of companion β-lactam antibiotics.

Diazabicyclooctane: A non-β-lactam chemical scaffold that forms stable, reversible adducts with serine β-lactamases, inhibiting their activity.

Penicillin-binding proteins (PBPs): Enzymes involved in the final stages of bacterial cell wall synthesis that are targeted by β-lactam antibiotics.

Multidrug-resistant (MDR): Bacterial strains that are non-susceptible to at least one agent in three or more antimicrobial categories.

Minimal inhibitory concentration (MIC): The lowest concentration of an antimicrobial that prevents visible bacterial growth under standardized conditions.

References

1. Durlobactam, a New Diazabicyclooctane β-Lactamase Inhibitor for the Treatment of Acinetobacter Infections in Combination With Sulbactam. Frontiers in Microbiology (2021).
2. In Vitro Activity of Sulbactam-Durlobactam against Global Isolates of Acinetobacter baumannii-calcoaceticus Complex Collected from 2016 to 2021. Antimicrobial Agents and Chemotherapy (2022).
3. Molecular drivers of resistance to sulbactam-durlobactam in contemporary clinical isolates of Acinetobacter baumannii. Antimicrobial Agents and Chemotherapy (2023).