Resolving the Mechanisms of Bacterial Resistance to Macrolide Antibiotics

Abstract

Macrolides are a class of commonly used antibiotics that target the bacterial ribosome and prevent protein synthesis in the affected cells. Ribosomal residues A2058 and G2505 in the protein exit channel are considered to be particularly important for macrolide binding. Unfortunately, due to extensive use of macrolides, bacterial resistance, caused by mutation or methylation of specific rRNA residues in the ribosome, has become a growing concern. How these changes in rRNA induce macrolide resistance on a molecular level is still unclear. Here, we investigated macrolide resistance using atomistic molecular dynamics simulations.Presently, there are no force field parameters developed specifically for macrolides. Therefore, we have developed novel approaches for force field parametrization from first principles for large and bulky molecules, such as macrolides, using the Force Field Tool Kit plugin in VMD. Parameters were developed and validated for two commonly used macrolides: erythromycin and azithromycin. These macrolides were studied in wild-type and in two mutated ribosomes of E. coli: G2057A and A2058G. The simulation showed that both mutations caused rearrangements of the binding site and decreased hydrogen bonding between the macrolide and residue 2058. Surprisingly, the G2057A mutation prevented hydrogen binding to residue 2058 to a larger extent than the A2058G mutation.