Universität zu Köln

Kavcic, Bor ORCID: 0000-0001-6041-254X, Tkacik, Gasper ORCID: 0000-0002-6699-1455 and Bollenbach, Tobias ORCID: 0000-0003-4398-476X (2020). Mechanisms of drug interactions between translation-inhibiting antibiotics. Nat. Commun., 11 (1). LONDON: NATURE PUBLISHING GROUP. ISSN 2041-1723

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Abstract

Antibiotics that interfere with translation, when combined, interact in diverse and difficult-to-predict ways. Here, we explain these interactions by translation bottlenecks: points in the translation cycle where antibiotics block ribosomal progression. To elucidate the underlying mechanisms of drug interactions between translation inhibitors, we generate translation bottlenecks genetically using inducible control of translation factors that regulate well-defined translation cycle steps. These perturbations accurately mimic antibiotic action and drug interactions, supporting that the interplay of different translation bottlenecks causes these interactions. We further show that growth laws, combined with drug uptake and binding kinetics, enable the direct prediction of a large fraction of observed interactions, yet fail to predict suppression. However, varying two translation bottlenecks simultaneously supports that dense traffic of ribosomes and competition for translation factors account for the previously unexplained suppression. These results highlight the importance of continuous epistasis in bacterial physiology. Antibiotics targeting protein translation interact in hard-to-predict ways. Here, Kavi et al. interpret these interactions in terms of translation bottlenecks, the kinetics of drug uptake and target binding, bacterial growth laws, and a model of queued traffic progression.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Kavcic, Bor UNSPECIFIED orcid.org/0000-0001-6041-254X UNSPECIFIED Tkacik, Gasper UNSPECIFIED orcid.org/0000-0002-6699-1455 UNSPECIFIED Bollenbach, Tobias UNSPECIFIED orcid.org/0000-0003-4398-476X UNSPECIFIED
URN:	urn:nbn:de:hbz:38-323481
DOI:	10.1038/s41467-020-17734-z
Journal or Publication Title:	Nat. Commun.
Volume:	11
Number:	1
Date:	2020
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	2041-1723
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Physics > Institut für Biologische Physik
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language ELONGATION-FACTOR G; ESCHERICHIA-COLI; RIBOSOMAL-RNA; FEEDBACK-REGULATION; PROTEIN-SYNTHESIS; GENE-EXPRESSION; GROWTH; TRANSCRIPTION; RESISTANCE; RESPONSES Multiple languages Multidisciplinary Sciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/32348