Carbapenem-Resistant Acinetobacter Baumannii (CRAB) is a pathogen with limited treatment options, representing a major global healthcare risk. In a study published in Nature, Zampaloni et al describe the development of a new class of antibiotics called tethered macrocyclic peptide (MCP) antibiotics. They also identify a new antibiotic candidate, zosurabalpin, which may be the first antibiotic capable of treating CRAB infections identified in over 50 years.
The new MCP class of antibiotics work by blocking the lipopolysaccharide transport machinery of pathogens by inhibiting the LptB2FGC complex. By blocking lipopolysaccharide transport, MCPs can kill Acinetobacter clinical isolates displaying a wide range of resistance mechanisms.
Based on preclinical data, in which zosurabalpin showcased favourable pharmacokinetics and safety, it was selected as the preferred candidate for further analysis. Zosurabalpin was able to treat drug-resistant CRAB in vitro. In mouse models, zosurabalpin overcame known antibiotic resistance mechanisms by effectively treating sepsis and thigh and lung infections caused by CRAB strains. Zosurabalpin may therefore address a critical need for a novel antibiotic that is not expected to be susceptible to existing mechanisms of resistance.
The potential of zosurabalpin as an antibiotic has prompted the initiation of human clinical trials, marking a significant step towards providing a viable treatment option for invasive infections caused by CRAB, which have a high mortality rate. As we continue to face the challenges of antibiotic resistance, these findings offer hope and a promising avenue for the development of much-needed alternatives in the fight against resilient bacterial infections.
This article is based on Zampaloni C, et al. Nature. 2024; online ahead of print. DOI: 10.1038/s41586-023-06873-0.
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