The chemistry of peptidyltransferase center-targeted antibiotics: enzymatic resistance and approaches to countering resistance

Abstract

The continued ability to treat bacterial infections requires effective antibiotics. The development of new therapeutics is guided by knowledge of the mechanisms of action of and resistance to these antibiotics. Continued efforts to understand and counteract antibiotic resistance mechanisms at a molecular level have the potential to direct development of new therapeutic strategies in addition to providing insight into the underlying biochemical functions impacted by antibiotics. The interaction of antibiotics with the peptidyltransferase center and adjacent exit tunnel within the bacterial ribosome is the predominant mechanism by which antibiotics impede translation, thus stalling growth. Resistance enzymes catalyze the chemical modification of the RNA that composes these functional regions, leading to diminished binding of antibiotics. This review discusses recent advances in the elucidation of chemical mechanisms underlying resistance and driving the development of new antibiotics.

Figure 1

PTC-targeting antibiotics.

Figure 2

RNA modifications and polar methylation mechanisms. a) Methylated bases, labeled with the modification and representative enzymes responsible for the transformation. Superscripts denote the position of modification on an RNA base; subscripts indicate the stoichiometry of methylation; 2′-O methylation is indicated by an m following the base that is ribose methylated. b) Mechanism of N-methylation by a SAM-dependent methyltransferase, e.g. Erm. c) Mechanism of C5 methylation by a SAM-dependent methyltransferase, e.g. RsmB. In both b and c, pt is used to indicate a proton transfer has taken place but is not shown explicitly.

Figure 3

Deuterium labeling patterns observed in RlmN and the proposed RlmN mechanism. a) The observed incorporation and retention of deuterium from various labeling experiments carried out with RlmN. b) The mechanism of catalysis by RlmN proposed by Grove et al (modified from reference 34).

Figure 4

Erythromycin and telithromycin bound to E. coli ribosomes. Critical residues are indicated. The RNA backbone is shown as an orange ribbon; the protein chain is shown as a gray ribbon. Erythromycin is colored fuschia and telithromycin is colored light blue. The figure was generated using Pymol from PDB files 3OAT and 3OFR.

Figure 5

Linezolid and torezolid in Deinococcus radiodurans ribosomes. The 8-methyl group on A2503 was modeled using Pymol. a) Linezolid is shown in fuschia (from PDB file 3DLL). b) Torezolid is shown in light blue; the acetamidomethyl pendant group of linezolid was replaced by the hydroxymethyl of torezolid in Pymol. The distance—in angstroms, demarcated by a dashed blue line—between the C-8 methyl on A2503 and the nearest heavy atom of the antibiotic is indicated in both a and b.