New Class of Antibiotics with a Novel Mode of Inhibition against World Health Organization’s Critical Listed Bacteria, Carbapenem-Resistant Acinetobacter baumannii

Lipopolysaccharides (LPS) present in the outer membrane of Gram-negative bacteria make them highly resilient to antibiotics. Hence, the transporter protein that transfers lipopolysaccharides from the cytoplasmic membrane to the outer surface has been one of the key potential target sites.

Fig 1. Schematic representation of the seven protein LPS transport machine (Image Source: Pahil et al., 2024)

Recently published papers elaborate on the discovery of a new class of macrocyclic peptide-based antibiotics capable of disrupting the transport of bacterial LPS from the inner membrane to the outer surface moving through the periplasmic space and outer membrane. Altogether all three identified compounds (1 (RO7196472); 2 (Zosurabalpin); 3 (RO707557) were capable of showing selective activity against Acinetobacter strains, including Carbapenem-resistant A. baumannii (CRAB).

Fig 2. Structures of macrocyclic peptides

The authors were able to demonstrate that the extensive contact between the LPS and its transporter during the transit resulting in the entrapment of LPS was the primary mode of inhibition by the peptides. However, the reason behind the selectivity of the compounds primarily against Acinetobacter strains, and not against other gram-negative bacteria remains elusive, although structural differences arising due to differences in protein structure have been suggested by the authors as one of the probable causes.

Of the three compounds identified, Zosurabalpin has already started its clinical trials. Preliminary results from the two completed clinical trials show that healthy participants showed overall well toleration to a single intravenous dose of 10 milligrams to 2000 mg of the drug and a well-behaved pharmacokinetics profile.

References:

Pahil, K.S., Gilman, M.S.A., Baidin, V. et al. A new antibiotic traps lipopolysaccharide in its intermembrane transporter. Nature (2024). https://doi.org/10.1038/s41586-023-06799-7

Zampaloni, C., Mattei, P., Bleicher, K. et al. A novel antibiotic class targeting the lipopolysaccharide transporter. Nature (2024). https://doi.org/10.1038/s41586-023-06873-0

Guenther A, Millar L, Messer A, Giraudon M, Patel K, Deurloo EJ, Lobritz M, Gloge A. 2126. Safety, Tolerability, and Pharmacokinetics (PK) in Healthy Participants Following Single Dose Administration of Zosurabalpin, a Novel Pathogen-Specific Antibiotic for the Treatment of Serious Acinetobacter Infections. Open Forum Infect Dis. 2023 Nov 27;10(Suppl 2):ofad500.1749. doi: 10.1093/ofid/ofad500.17491749. PMCID: PMC10678405.