LAUSR

Macrolides, which bind in the protein exit tunnel of the bacterial ribosome, are one of the most prescribed classes of antibiotics.However, macrolide resistance caused by ribosomal modifications at base A2058 in segment 23S is a growing problem. It has been foundthat attachment of aromatic moieties can increasemacrolide activity against both wild-type and macrolide-resistant ribosomes due to additional aromatic interactions with rRNA, resulting in new antibiotics, e.g., telithromycin. Our previous simulations of the stalling peptideSecM in the ribosome revealed stable aromatic interactions between residue W155 in SecM and base A751 in segment23S, inspiring the development of azithromycin derivatives containing indole-analog moieties that could mimic these interactions. Several of these derivatives showed improved activity against wild-typeEscherichia coli compared to azithromycin, although, a better understanding of the structure-activity relationship for the different moietiesis needed for further improvement.Here, we used molecular dynamics simulations to study erythromycin and azithromycin in wild-type and A2058-modified, E. coli ribosomes. The ribosomal modifications resulted in less favorable interactions between base 2058 and the desosamine sugar of the macrolides as well as a greater displacement of the macrolides, explaining the causes for resistance. Additionally, two of the azithromycin derivatives noted above were simulated in the wild-type ribosome. We found that the added indole-analog moieties adopted different geometries when interacting with base A751, which could explain the differences in their activity. Our results illustrate the utility of MD simulations in the design of a new generation of macrolides that can overcome bacterial resistance.