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Ribosome-targeting antibiotics and mechanisms of bacterial resistance

Key Points

  • The bacterial ribosome is one of the main targets of antibiotics, with most clinically used antibiotics targeting either the decoding site on the small ribosomal subunit (30S subunit) or the peptidyl-transferase centre on the large subunit (50S subunit).

  • The majority of antibiotics that target the 30S subunit inhibit protein synthesis by preventing either the binding of tRNAs to the ribosome or the movement of tRNAs through the ribosome during translocation.

  • Most antibiotics that target the 50S subunit inhibit protein synthesis by either perturbing the binding of aminoacylated-tRNAs at the A- or P-sites or preventing the channelling of the nascent polypeptide chain through the ribosomal tunnel.

  • Bacterial antibiotic resistance mechanisms include efflux, reduced influx, modification and degradation of the drug, as well as mutation, modification or overexpression of the target.

  • The majority of ribosome-targeting antibiotics in clinical trials are semi-synthetic derivatives of naturally produced compounds, but further work will be required to develop antibiotics that target novel sites on the ribosome.

Abstract

The ribosome is one of the main antibiotic targets in the bacterial cell. Crystal structures of naturally produced antibiotics and their semi-synthetic derivatives bound to ribosomal particles have provided unparalleled insight into their mechanisms of action, and they are also facilitating the design of more effective antibiotics for targeting multidrug-resistant bacteria. In this Review, I discuss the recent structural insights into the mechanism of action of ribosome-targeting antibiotics and the molecular mechanisms of bacterial resistance, in addition to the approaches that are being pursued for the production of improved drugs that inhibit bacterial protein synthesis.

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Figure 1: Antibiotic target sites during bacterial protein synthesis.
Figure 2: Antibiotic binding sites on the 30S and 50S ribosomal subunits.
Figure 3: Antibiotic interactions at the decoding centre of the 30S subunit.
Figure 4: Antibiotic interactions at the peptidyl-transferase centre of the 50S subunit.
Figure 5: Antibacterial resistance mechanisms.

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Acknowledgements

I give special thanks to A. Mankin, B. Beatrix and members of my laboratory for critical reading of the manuscript. I also thank the Deutsche Forschungsgemeinschaft (WI3285/2-1) and the EMBO young investigator grant for funding research related to this topic.

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Glossary

Peptidyl-transferase centre

(PTC). The site of peptide-bond formation on the large subunit, comprising universally conserved residues of domain V of the 23S ribosomal RNA.

Classical tRNA state

The tRNA binding state in which the anticodon and acceptor arms of the tRNA occupy the same sites on the 30S and 50S subunit, respectively.

Stacking interaction

Non-covalent interaction established by parallel plate stacked orientation of two moieties, with at least one being aromatic.

Non-cognate tRNAs

tRNAs that have a mismatched base-pairing interaction with mRNA codons. Accommodation leads to misincorporation of an incorrect amino acid into the nascent polypeptide chain.

Decoding centre

The A-site region of the small ribosomal subunit that is responsible for discriminating cognate from non-cognate tRNAs based on anticodon–codon interactions. This site encompasses the universally conserved nucleotides A1492 and A1493 of helix 44 of the 16S rRNA.

Cognate tRNAs

tRNAs that have a matched base-pairing interaction with mRNA codons. Accommodation leads to incorporation of the correct amino acid into the nascent polypeptide chain.

Intersubunit bridges

Sites of interaction at the interface between the small and large ribosomal subunits.

Hybrid state

The tRNA binding state in which the anticodon and acceptor arms of the tRNA occupy different sites on the 30S and 50S subunit, respectively.

Peptidyl-tRNA drop-off

Dissociation of tRNAs bearing the nascent polypeptide chain from the ribosome.

Bacteriocidal

Bacteriocidal antibiotics induce cell death, as exemplified by the aminoglycoside class of ribosome-targeting antibiotics.

Bacteriostatic

Bacteriostatic antibiotics inhibit bacterial growth but do not induce cell death, such that removal of the antibiotic leads to restoration of growth. Most ribosome-targeting antibiotics are bacteriostatic.

MATE family of transporters

(Multidrug and toxic compound extrusion family of transporters). MATE transporters couple antibiotic efflux (against their prevailing concentration gradient) to the energetically favourable movement of sodium ions (Na+) into the cell (along their electrochemical gradient).

Porins

β-barrel proteins that span the cell membrane and act as pores through which molecules can diffuse.

Compensatory mutations

In the context of this Review, secondary mutations that arise to restore bacterial fitness following a decrease in fitness owing to antibiotic resistance mutations.

Translation profiles

An indication of the changes in the levels of synthesis of proteins by ribosomes.

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Wilson, D. Ribosome-targeting antibiotics and mechanisms of bacterial resistance. Nat Rev Microbiol 12, 35–48 (2014). https://doi.org/10.1038/nrmicro3155

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