The chemistry of peptidyltransferase center-targeted antibiotics: enzymatic resistance and approaches to countering resistance.
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.
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, 94158, United States.
Kevin P
KP
McCusker
Danica Galonić
DG
Fujimori
D000081:Acetamides / Q000737:chemistry / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D001424:Bacterial Infections / Q000188:drug therapy / Q000382:microbiology; D001665:Binding Sites; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects; D004917:Erythromycin / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D000069349:Linezolid; D008745:Methylation; D023303:Oxazolidinones / Q000737:chemistry / Q000494:pharmacology; D010458:Peptidyl Transferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects*; D012338:RNA, Ribosomal, 23S / Q000378:metabolism*; D012270:Ribosomes / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D013777:Tetrazoles / Q000737:chemistry / Q000494:pharmacology
D000081:Acetamides; D000900:Anti-Bacterial Agents; D023303:Oxazolidinones; D012338:RNA, Ribosomal, 23S; D013777:Tetrazoles; D004917:Erythromycin; C546016:tedizolid; D010458:Peptidyl Transferases; D000069349:Linezolid