Toward the rational design of macrolide antibiotics to combat resistance
Abstract
Here, 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.
- Authors:
-
- Georgia Inst. of Technology, Atlanta, GA (United States)
- Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
- Publication Date:
- Research Org.:
- Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
- Sponsoring Org.:
- USDOE
- OSTI Identifier:
- 1376364
- Grant/Contract Number:
- AC05-00OR22725
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Chemical Biology & Drug Design
- Additional Journal Information:
- Journal Volume: 90; Journal Issue: 5; Journal ID: ISSN 1747-0277
- Publisher:
- Wiley
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 60 APPLIED LIFE SCIENCES; 59 BASIC BIOLOGICAL SCIENCES; antibiotics; drug design; macrolides; molecular modeling; ribosome
Citation Formats
Pavlova, Anna, Parks, Jerry M., Oyelere, Adegboyega K., and Gumbart, James C. Toward the rational design of macrolide antibiotics to combat resistance. United States: N. p., 2017.
Web. doi:10.1111/cbdd.13004.
Pavlova, Anna, Parks, Jerry M., Oyelere, Adegboyega K., & Gumbart, James C. Toward the rational design of macrolide antibiotics to combat resistance. United States. https://doi.org/10.1111/cbdd.13004
Pavlova, Anna, Parks, Jerry M., Oyelere, Adegboyega K., and Gumbart, James C. Mon .
"Toward the rational design of macrolide antibiotics to combat resistance". United States. https://doi.org/10.1111/cbdd.13004. https://www.osti.gov/servlets/purl/1376364.
@article{osti_1376364,
title = {Toward the rational design of macrolide antibiotics to combat resistance},
author = {Pavlova, Anna and Parks, Jerry M. and Oyelere, Adegboyega K. and Gumbart, James C.},
abstractNote = {Here, 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.},
doi = {10.1111/cbdd.13004},
journal = {Chemical Biology & Drug Design},
number = 5,
volume = 90,
place = {United States},
year = {Mon Apr 17 00:00:00 EDT 2017},
month = {Mon Apr 17 00:00:00 EDT 2017}
}
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