The chemical optimization of the arylomycin class of natural products into a compound with potent, broad-spectrum activity against multidrug-resistant infections of Gram-negative bacteria, such as E. coli, is reported this week in Nature. These findings, in cells and mice, may pave the way to develop these compounds into essential new drugs to combat a serious risk to global health.
Multidrug-resistant bacteria are spreading, and the ESKAPE pathogens present the most acute risk of untreatable multidrug-resistant infections. The Gram-negative members of this group (Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii), which have a dual membrane envelope that prevents many antibiotics from accessing their targets, pose a particular threat. Despite extensive efforts, no new antibiotic class with activity against Gram-negative bacteria has been approved in over 50 years.
The arylomycins are a class of macrocyclic lipopeptides that inhibit bacterial type I signal peptidase (SPase), an essential membrane-bound enzyme that breaks down proteins and peptides. In Gram-negative bacteria, the active site of SPase is located between the cytoplasmic and the outer membranes. This active site was believed to be inaccessible to the arylomycins, as it was thought that they could not penetrate the outer membrane.
Christopher Heise and colleagues sought to identify arylomycin derivatives with increased target affinity and improved ability to penetrate outer membranes. The authors discovered a synthetic arylomycin derivative, called G0775, with potent antibacterial activity against the ESKAPE pathogens in the lab. They also observed that G0775 uses an atypical mechanism to penetrate outer membranes. The authors found that highly multidrug-resistant pathogens that are resistant to nearly all available antibiotic therapies remain susceptible to G0775, to which resistance occurs at a low frequency. The efficacy of G0775 against Gram-negative pathogens was confirmed in multiple mouse models of infection.