The Novel Modes of Action of Ribosomal Antibiotics
thesisposted on 28.06.2013, 00:00 by Krishna Kannan
Ribosome, a macromolecular machine that synthesizes proteins inside all living cells, is one of the biggest targets for small molecules called antibiotics. Several antibiotics, commonly used to treat bacterial infections, bind to ribosomes, inhibit their function and consequently, cell growth. Several decades of extensive studies have facilitated the delineation of the mechanism of action of all the clinically used ribosomal antibiotics. Although the currently established mode with which most antibiotics act is well accepted, we discovered that drugs belonging different classes deviate significantly from their expected behavior. Specifically, we found that drugs from the macrolide class do not inhibit synthesis of all cellular proteins even at very high concentrations, contrasting the previous beliefs. In fact, the spectrum of proteins that escape inhibition by these drugs determine the potency of these antibiotics in terms of bacterial killing activity. Our studies with the macrolide antibiotics suggest that targeting designated proteins for inhibition by small molecules can result in the discovery of better antibiotics rather than exploring compounds that globally shut down cellular protein synthesis. Separately, we established a new mode of action of other classes of clinically important antibiotics such as phenicols and oxazolidinones. Drugs belonging to the aforementioned classes inhibit protein synthesis at specific stages in a ‘context-specific’ manner. Collectively, our studies illuminate the novel mechanisms by which several clinically important antibiotics act and could eventually assist in the development of more potent antimicrobials.