Editor’s summary
Many small-molecule antibiotics target the bacterial ribosome, and there are many corresponding ribosome modifications that confer resistance by reducing the binding affinity of these molecules. One way to boost their affinity would be to lock these molecules in an ideal conformation for binding. Wu et al. used insights from structural analysis of ribosomes bound to previously developed antibiotics to design a conformationally restricted molecule, dubbed cresomycin, that adopts the exact conformation necessary for binding. Computational, structural, and biochemical experiments confirmed the expected binding mode. Cresomycin potently inhibits Gram-negative and -positive bacteria, including multi-drug-resistant strains, both in vitro and in a mouse infection model. —Michael A. Funk
Abstract
We report the design conception, chemical synthesis, and microbiological evaluation of the bridged macrobicyclic antibiotic cresomycin (CRM), which overcomes evolutionarily diverse forms of antimicrobial resistance that render modern antibiotics ineffective. CRM exhibits in vitro and in vivo efficacy against both Gram-positive and Gram-negative bacteria, including multidrug-resistant strains of Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa. We show that CRM is highly preorganized for ribosomal binding by determining its density functional theory–calculated, solution-state, solid-state, and (wild-type) ribosome-bound structures, which all align identically within the macrobicyclic subunits. Lastly, we report two additional x-ray crystal structures of CRM in complex with bacterial ribosomes separately modified by the ribosomal RNA methylases, chloramphenicol-florfenicol resistance (Cfr) and erythromycin-resistance ribosomal RNA methylase (Erm), revealing concessive adjustments by the target and antibiotic that permit CRM to maintain binding where other antibiotics fail.
