Structural basis for plazomicin antibiotic action and resistance

The approval of plazomicin broadened the clinical library of aminoglycosides available for use against emerging bacterial pathogens. Contrarily to other aminoglycosides, resistance to plazomicin is limited; still, instances of resistance have been reported in clinical settings. Here, we present structural insights into the mechanism of plazomicin action and the mechanisms of clinical resistance. The structural data reveal that plazomicin exclusively binds to the 16S ribosomal A site, where it likely interferes with the fidelity of mRNA translation. The unique extensions to the core aminoglycoside scaffold incorporated into the structure of plazomicin do not interfere with ribosome binding, which is analogously seen in the binding of this antibiotic to the AAC(2)-Ia resistance enzyme. The data provides a structural rationale for resistance conferred by drug acetylation and ribosome methylation, i.e., the two mechanisms of resistance observed clinically. Finally, the crystal structures of plazomicin in complex with both its target and the clinically relevant resistance factor provide a roadmap for next-generation drug development that aims to ameliorate the impact of antibiotic resistance. Golkar, Bassenden et al. report two structures of the latest generation aminoglycoside antibiotic plazomicin in complex with the bacterial 70S ribosome as well as in complex with AAC(2')-la acetyltransferase, an antibiotic modification enzyme (AME). Their study can be useful in the development of newer aminoglycosides that are not modified by AMEs while being capable of targeting the bacterial ribosome.

Automated summary

The approval of plazomicin broadened the clinical library of aminoglycosides available for use against emerging bacterial pathogens, but resistance to plazomicin has been reported in clinical settings. Structural insights into the mechanism of plazomicin action and clinical resistance mechanisms provide a roadmap for next-generation drug development. The study of plazomicin structures in complex with the bacterial ribosome and antibiotic modification enzyme can be useful in the development of newer non-modified aminoglycosides capable of targeting the bacterial ribosome.