Toward the rational design of macrolide antibiotics to combat resistance

5 years ago

Toward the rational design of macrolide antibiotics to combat resistance

Jerry M. Parks, James C. Gumbart, Adegboyega K. Oyelere, Anna Pavlova

Macrolides, one of the most prescribed classes of antibiotics, bind in the bacterial ribosome's polypeptide exit tunnel and inhibit translation. However, mutations and other ribosomal modifications, especially to the base A2058 of the 23S rRNA, have led to a growing resistance problem. Here, we have used molecular dynamics simulations to study the macrolides erythromycin and azithromycin in wild-type, A2058G-mutated, and singly or doubly A2058-methylated Escherichia coli ribosomes. We find that the ribosomal modifications result in less favorable interactions between the base 2058 and the desosamine sugar of the macrolides, as well as greater displacement of the macrolides from their crystal structure position, illuminating the causes of resistance. We have also examined four azithromycin derivatives containing aromatic indole-analog moieties, which were previously designed based on simulations of the stalling peptide SecM in the ribosome. Surprisingly, we found that the studied moieties could adopt very different geometries when interacting with a key base in the tunnel, A751, possibly explaining their distinct activities. Based on our simulations, we propose modifications to the indole-analog moieties that should increase their interactions with A751 and, consequently, enhance the potency of future azithromycin derivatives. The molecular causes of resistance to macrolide antibiotics by bacterial ribosomes are examined with MD simulations. Novel macrolide derivatives exploiting a conserved, functionally relevant interaction are also explored, and suggestions for further improvement are given.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1111/cbdd.13004