Poster abstracts
Poster number 114 submitted by Maxim Svetlov
Kinetics of drug-ribosome interactions defines the cidality of macrolide antibiotics
Maxim Svetlov (University of Illinois at Chicago), Nora-Vazquez Laslop (University of Illinois at Chicago), Alexander Mankin (University of Illinois at Chicago)
Abstract:
Ribosome is a large ribonucleoprotein particle responsible for the synthesis of all proteins in a living cell. Due to its vital role, ribosome is one of the main antibiotic targets in bacteria. It is well known that the interaction of antibiotic with its target molecule can cause dormancy (bacteriostasis) or induce death (cidality) of bacteria. The bactericidal capacity is one of the most critical characteristics of antibacterial agents. However, the current understanding of the fundamental differences in the binding or action of bacteriostatic and bactericidal antibiotics is very rudimentary. Here, by examining the action of several structurally related but chemically distinct ribosome-targeting bacteriostatic and bactericidal macrolide inhibitors we have identified a key difference, which correlates with the ability of the drugs to cause cell death. While bacteriostatic and bactericidal macrolide antibiotics, which bind in the nascent peptide exit tunnel, exhibit comparable affinity to the ribosome, the bactericidal antibiotics are characterized by a significantly slower dissociation rates. The presence and the nature of an extended alkyl-aryl side chain in the macrolide structure, which establishes idiosyncratic interactions with the ribosome, are essential for the characteristically slow rate of dissociation of bactericidal inhibitors. Importantly, low level of residual translation in cells treated with normally bactericidal antibiotics can protect cells from killing even at concentrations of the drugs that significantly exceed those required for cell growth arrest. On the basis of our findings, we propose a new conceptual framework for explaining difference in cidality of antibiotics of the same class.
Keywords: ribosome, macrolides, bactericidal antibiotics