Antibiotic with novel mechanism offers new hope for treating resistant infections

This week saw the publication of a potential new class of antibiotics and their mechanism (Zampaloni et al., 2024, Pahil et al., 2024).

The news is met with excitement in the field due to the importance and rarity of novel antibiotic classes making it to the clinic.

It has been around two decades since a new class of antibiotics with activity against any pathogen made it to patients. The WHO estimates that there are currently 77 new antibacterial treatments in clinical development as of mid-2023, with the vast majority being new iterations of existing antibiotics rather than potential new classes.

Acinetobacter baumannii has proved a particularly difficult target for new antibiotic development, with no new approved antibiotics reaching patients for over 50 years. A. baumannii is an opportunistic pathogen, most commonly causing hospital-acquired pneumonia and bloodstream infections. Concerningly, recent surveillance shows increasing reports of pan-resistant strains across the globe – with high associated mortality. It is therefore no surprise that A. baumannii remains critically important on the WHO’s priority pathogen list.

Zosurabalpin and two other macrocyclic peptides were found in this recent work which excitingly have potent antibacterial activity against carbapenem-resistant A. baumannii (CRAB).

A novel mechanism to treat resistant strains

The macrocyclic peptides developed by Roche, including zosurabalpin and two other candidates, have a novel mechanism of action involving blocking the transport of the key component of Gram-negative bacterial membranes to the external surface of the cell.

Seven lipopolysaccharide transport (Lpt) proteins bridge the two membranes of Gram-negative bacteria such as A. baumannii, Pseudomonas aeruginosa, and Enterobacteriaceae like E. coli.

The new mechanism of action of zosurabalpin blocks the transport of lipopolysaccharide (LPS) after its synthesis inside the bacterium, to its desired position where it forms the outermost protective surface of the cell. It is thought that the resulting accumulation of LPS intermediates is toxic to the bacterium, resulting in cell death.

What’s next?

With zosurabalpin now having entered human clinical trials, we wait with fingers crossed to see how this promising candidate progresses.