Cresomycin – a novel synthetic molecule – demonstrates remarkably robust efficacy against multiple, evolutionary divergent forms of antimicrobial resistance (AMR), researchers report. The emergence and widespread distribution of bacteria broadly resistant to approved antibiotics raises serious global public health concerns. Given the growing rate of deaths attributable to antimicrobial resistance (AMR) worldwide, it’s evident the pace of discovery and development of antibiotics effective against AMR has not kept up with the need. Many small molecule antibiotics, like clindamycin, target the bacterial ribosome. As a result, bacterial evolution has produced many corresponding ribosome modifications that confer resistance by reducing the binding affinity of these antibiotic molecules. One way to overcome this challenge and design an antibiotic that responds to the evolutionarily diverse forms of antimicrobial resistance that render modern antibiotics ineffective is to design an antibiotic molecule with a structure that is preorganized for optimal ribosomal binding. Using insights from the structural analysis of antibiotics bound to ribosomes of diverse bacterial species, Kelvin Wu and colleagues developed a novel conformally restricted antibiotic molecule they call cresomycin, which adopts the exact conformation needed for ribosomal binding. Wu et al. confirmed the expected binding mode using various computational, structural, and biochemical approaches. Moreover, the authors show that cresomycin potentially inhibits Gram-negative and -positive bacteria, including multi-drug resistant strains of Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa both in vitro and in a mouse infection model. “We do not suggest that CRM is fully optimized for inhibition of the bacterial ribosome, for in view of the innumerable macrobicyclic structural and substantial variants that can be conceived by have not yet been explored, that would be statistically improbable,” write Wu et al . “Although that is perhaps a daunting consideration, we believe that our findings portend favorably for the future discovery of antibacterial agents broadly effective against AMR.”
Science
An antibiotic preorganized for ribosomal binding overcomes antimicrobial resistance
16-Feb-2024