Zosurabalpin: an antibiotic with a new mechanism of action against carbapenem-resistant Acinetobacter baumannii

Abstract

Background: Carbapenem-resistant Acinetobacter baumannii (CRAB) poses a critical global health threat, particularly among hospitalized and critically ill patients, due to its association with severe, difficult-to-treat infections. Its high resistance stems from genomic plasticity, biofilm formation, and environmental persistence, leading to limited treatment options and high mortality. Existing treatments often rely on sulbactam-based combinations, yet resistance continues to rise and new agents remain limited.

Aims: This review aims to highlight the therapeutic potential of zosurabalpin, a first-in-class lipopolysaccharide (LPS) transport inhibitor with selective activity against A. baumannii, by summarizing preclinical and early clinical data on its efficacy, mechanism of action, pharmacokinetics, and safety.

Sources: Peer-reviewed publications from PubMed and Scopus, clinical data from ClinicalTrials.gov, and relevant conference materials ECCMID and IDWeek.

Content: Zosurabalpin inhibits the LptB-FGC complex, blocking LPS transport and causing lethal intracellular accumulation. Preclinical data demonstrate potent in vitro and in vivo activity against CRAB, with high selectivity and favorable pharmacokinetics. Phase 1 studies report good tolerability and a promising safety profile.Its novel mechanism makes zosurabalpin a strong candidate for treating CRAB.

Implications: With rising resistance and limited effective treatments, zosurabalpin offers a new, targeted therapeutic approach. Continued clinical development could help close a critical gap in the management of multidrug-resistant Acinetobacter baumannii.

Keywords: Carbapenem-resistant Acinetobacter baumannii (CRAB); LPS transport inhibitors; lipopolysaccharide (LPS) transport system; zosurabalpin.

Figure 1

Mechanism of action of zosurabalpin through inhibition of the LptB₂FGC transporter complex in Acinetobacter baumannii (based on concepts and structures described in references [18], [21], [–24]).