Bacterial drug resistance overcome by synthetic restructuring of antibiotics

The discovery and implementation of antibiotics in the early twentieth century transformed human health and wellbeing. Chemical synthesis enabled the development of the first antibacterial substances, organoarsenicals and sulfa drugs, but these were soon outshone by a host of more powerful and vastly more complex antibiotics from nature: penicillin, streptomycin, tetracycline, and erythromycin, among others. These primary defences are now significantly less effective as an unavoidable consequence of rapid evolution of resistance within pathogenic bacteria, made worse by widespread misuse of antibiotics. For decades medicinal chemists replenished the arsenal of antibiotics by semisynthetic and to a lesser degree fully synthetic routes, but economic factors have led to a subsidence of this effort, which places society on the precipice of a disaster. We believe that the strategic application of modern chemical synthesis to antibacterial drug discovery must play a critical role if a crisis of global proportions is to be averted.

Many antibiotics inhibit bacterial growth by binding to the ribosome and interfering with protein biosynthesis. Macrolides represent one of the most successful classes of ribosome-targeting antibiotics. The main clinically-relevant mechanism of resistance to macrolides is dimethylation of the 23S rRNA nucleotide A2058 located in the drug binding site, a reaction catalyzed by the Erm-type rRNA-methyltransferases. Here, we present the crystal structure of the Erm-dimethylated 70S ribosome at 2.4Å resolution together with the structures of unmethylated 70S ribosome functional complexes alone and in combination with macrolides. Altogether, our structural data do not support the previous models and, instead, suggest a principally new explanation of how A2058-dimethylation confers resistance to macrolides. Moreover, high-resolution structures of two macrolide antibiotics bound to the unmodified ribosome revealed a previously unknown role of desosamine moiety in drug binding, laying a foundation for the rational knowledge-based design of macrolides that can overcome Erm-mediated resistance.