The ABC of Ribosome-Related Antibiotic Resistance

Abstract

The increase in multidrug-resistant pathogenic bacteria is limiting the utility of our current arsenal of antimicrobial agents. Mechanistically understanding how bacteria obtain antibiotic resistance is a critical first step to the development of improved inhibitors. One common mechanism for bacteria to obtain antibiotic resistance is by employing ATP-binding cassette (ABC) transporters to actively pump the drug from the cell. The ABC-F family includes proteins conferring resistance to a variety of clinically important ribosome-targeting antibiotics; however, controversy remains as to whether resistance is conferred via efflux like other ABC transporters or whether another mechanism, such as ribosome protection, is at play. A recent study by Sharkey and coworkers (L. K. Sharkey, T. A. Edwards, and A. J. O'Neill, mBio 7:e01975-15, 2016, http://dx.doi.org/10.1128/mBio.01975-15) provides strong evidence that ABC-F proteins conferring antibiotic resistance utilize ribosome protection mechanisms, namely, by interacting with the ribosome and displacing the drug from its binding site, thus revealing a novel role for ABC-F proteins in antibiotic resistance.

FIG 1

Interaction of ABC proteins with the ribosome. (A) Overview of the binding site of EttA (red) on the ribosome (white, RNA; gray, proteins) (12) relative to P-tRNA (blue) and A-tRNA (green). The small ribosomal subunit is omitted for clarity. (B) The linker region of EttA approaches but cannot access the PTC of the ribosome, where the CCA end of P-tRNA (blue), A-tRNA, and antibiotics, such as lincomycin (LIN [blue]) (17), interact. (C) Relative binding positions of EF-3 (13) and Rli1 (14) on the ribosome relative to A- and P-tRNAs.