Open Access
Proceedings of the National Academy of Sciences of the United States of America, volume 114, issue 52, pages 13673-13678
Kinetics of drug–ribosome interactions defines the cidality of macrolide antibiotics
Publication type: Journal Article
Publication date: 2017-12-11
Quartile SCImago
Q1
Quartile WOS
Q1
Impact factor: 11.1
ISSN: 00278424, 10916490
PubMed ID:
29229833
Multidisciplinary
Abstract
Significance Ribosome-targeting macrolide antibiotics can be bacteriostatic or bactericidal. What distinguishes the action of bactericidal macrolides from that of bacteriostatic compounds is unclear. We found that neither the residual translation in the macrolide-treated cells nor the affinity of the inhibitors explain the static/cidal distinction. Instead, bactericidal compounds show a markedly decreased rate of dissociation from the ribosome because of the presence of an extended side chain in their structure. The prolonged translation downtime caused by the slow rate of antibiotic clearance could bring the cell to a point of no return due to depletion of the factors critical for resumption of gene expression. Optimizing the kinetics of binding/dissociation rather than only the affinity could facilitate the development of bactericidal inhibitors of translation. Antibiotics can cause dormancy (bacteriostasis) or induce death (cidality) of the targeted bacteria. The bactericidal capacity is one of the most important properties of antibacterial agents. However, the understanding of the fundamental differences in the mode of action of bacteriostatic or bactericidal antibiotics, especially those belonging to the same chemical class, is very rudimentary. Here, by examining the activity and binding properties of chemically distinct macrolide inhibitors of translation, we have identified a key difference in their interaction with the ribosome, which correlates with their ability to cause cell death. While bacteriostatic and bactericidal macrolides bind in the nascent peptide exit tunnel of the large ribosomal subunit with comparable affinities, the bactericidal antibiotics dissociate from the ribosome with significantly slower rates. The sluggish dissociation of bactericidal macrolides correlates with the presence in their structure of an extended alkyl-aryl side chain, which establishes idiosyncratic interactions with the ribosomal RNA. Mutations or chemical alterations of the rRNA nucleotides in the drug binding site can protect cells from macrolide-induced killing, even with inhibitor concentrations that significantly exceed those required for cell growth arrest. We propose that the increased translation downtime due to slow dissociation of the antibiotic may damage cells beyond the point where growth can be reinitiated upon the removal of the drug due to depletion of critical components of the gene-expression pathway.
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1 publication, 2.08%
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- We do not take into account publications that without a DOI.
- Statistics recalculated only for publications connected to researchers, organizations and labs registered on the platform.
- Statistics recalculated weekly.
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Svetlov M. S., Vázquez Laslop N., Mankin A. S. Kinetics of drug–ribosome interactions defines the cidality of macrolide antibiotics // Proceedings of the National Academy of Sciences of the United States of America. 2017. Vol. 114. No. 52. pp. 13673-13678.
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Svetlov M. S., Vázquez Laslop N., Mankin A. S. Kinetics of drug–ribosome interactions defines the cidality of macrolide antibiotics // Proceedings of the National Academy of Sciences of the United States of America. 2017. Vol. 114. No. 52. pp. 13673-13678.
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TY - JOUR
DO - 10.1073/pnas.1717168115
UR - https://doi.org/10.1073%2Fpnas.1717168115
TI - Kinetics of drug–ribosome interactions defines the cidality of macrolide antibiotics
T2 - Proceedings of the National Academy of Sciences of the United States of America
AU - Svetlov, Maxim S
AU - Vázquez Laslop, Nora
AU - Mankin, Alexander S.
PY - 2017
DA - 2017/12/11 00:00:00
PB - Proceedings of the National Academy of Sciences (PNAS)
SP - 13673-13678
IS - 52
VL - 114
PMID - 29229833
SN - 0027-8424
SN - 1091-6490
ER -
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@article{2017_Svetlov,
author = {Maxim S Svetlov and Nora Vázquez Laslop and Alexander S. Mankin},
title = {Kinetics of drug–ribosome interactions defines the cidality of macrolide antibiotics},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
year = {2017},
volume = {114},
publisher = {Proceedings of the National Academy of Sciences (PNAS)},
month = {dec},
url = {https://doi.org/10.1073%2Fpnas.1717168115},
number = {52},
pages = {13673--13678},
doi = {10.1073/pnas.1717168115}
}
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MLA
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Svetlov, Maxim S., et al. “Kinetics of drug–ribosome interactions defines the cidality of macrolide antibiotics.” Proceedings of the National Academy of Sciences of the United States of America, vol. 114, no. 52, Dec. 2017, pp. 13673-13678. https://doi.org/10.1073%2Fpnas.1717168115.