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.
Subject(s)
Anti-Bacterial Agents , Bridged-Ring Compounds , Drug Resistance, Multiple, Bacterial , Lincosamides , Oxepins , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Erythromycin/chemistry , Erythromycin/pharmacology , Microbial Sensitivity Tests , Staphylococcus aureus/drug effects , Escherichia coli/drug effects , Pseudomonas aeruginosa/drug effects , Bridged-Ring Compounds/chemical synthesis , Bridged-Ring Compounds/chemistry , Bridged-Ring Compounds/pharmacology , Oxepins/chemical synthesis , Oxepins/chemistry , Oxepins/pharmacology , Lincosamides/chemical synthesis , Lincosamides/chemistry , Lincosamides/pharmacology , Animals , Mice , Drug Design , Ribosomes/chemistryABSTRACT
The development of a flexible, component-based synthetic route to the amino sugar fragment of the lincosamide antibiotics is described. This route hinges on the application and extension of nitroaldol chemistry to forge strategic bonds within complex amino sugar targets and employs a glycal epoxide as a versatile glycosyl donor for the installation of anomeric groups. Through building-block exchange and late-stage functionalization, this route affords access to a host of rationally designed lincosamides otherwise inaccessible by semisynthesis and underpins a platform for the discovery of new lincosamide antibiotics.