An Analysis of the Novel Fluorocycline TP-6076 Bound to Both the Ribosome and Multidrug Efflux Pump AdeJ from Acinetobacter baumannii
Abstract
Antibiotic resistance among bacterial pathogens continues to pose a serious global health threat. Multidrug-resistant (MDR) strains of the Gram-negative organism Acinetobacter baumannii utilize a number of resistance determinants to evade current antibiotics. One of the major resistance mechanisms employed by these pathogens is the use of multidrug efflux pumps. These pumps extrude xenobiotics directly out of bacterial cells, resulting in treatment failures when common antibiotics are administered. Here, the structure of the novel tetracycline antibiotic TP-6076, bound to both the Acinetobacter drug efflux pump AdeJ and the ribosome from Acinetobacter baumannii, using single-particle cryo-electron microscopy (cryo-EM), is elucidated. In this work, the structure of the AdeJ–TP-6076 complex is solved, and we show that AdeJ utilizes a network of hydrophobic interactions to recognize this fluorocycline. Concomitant with this, we elucidate three structures of TP-6076 bound to the A. baumannii ribosome and determine that its binding is stabilized largely by electrostatic interactions. We then compare the differences in binding modes between TP-6076 and the related tetracycline antibiotic eravacycline in both targets. These differences suggest that modifications to the tetracycline core may be able to alter AdeJ binding while maintaining interactions with the ribosome. Together, this work highlights how different mechanisms are usedmore »
- Authors:
-
[2];
[1]
- Case Western Reserve Univ., Cleveland, OH (United States). School of Medicine
- Louis Stokes Cleveland VA Medical Center, Cleveland, OH (United States)
- Publication Date:
- Research Org.:
- Pacific Northwest National Laboratory (PNNL), Richland, WA (United States). Environmental Molecular Sciences Laboratory (EMSL)
- Sponsoring Org.:
- USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF); National Institutes of Health (NIH); Cleveland Department of Veterans Affairs; USDOE Office of Science (SC), Biological and Environmental Research (BER)
- OSTI Identifier:
- 1982984
- Grant/Contract Number:
- AC05-76RL01830; R01AI145069; R01AI154860; R01AI157208; R01AI100560; R01AI063517; R01AI072219; 1I01BX001974; U24GM129547
- Resource Type:
- Accepted Manuscript
- Journal Name:
- mBio (Online)
- Additional Journal Information:
- Journal Name: mBio (Online); Journal Volume: 13; Journal Issue: 1; Journal ID: ISSN 2150-7511
- Publisher:
- American Society for Microbiology (ASM)
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 36 MATERIALS SCIENCE; Microbiology; Acinetobacter baumannii; AdeJ; TP-6076; Multidrug efflux pump; Multidrug resistance; Ribosomes
Citation Formats
Morgan, Christopher E., Zhang, Zhemin, Bonomo, Robert A., and Yu, Edward W. An Analysis of the Novel Fluorocycline TP-6076 Bound to Both the Ribosome and Multidrug Efflux Pump AdeJ from Acinetobacter baumannii. United States: N. p., 2022.
Web. doi:10.1128/mbio.03732-21.
Morgan, Christopher E., Zhang, Zhemin, Bonomo, Robert A., & Yu, Edward W. An Analysis of the Novel Fluorocycline TP-6076 Bound to Both the Ribosome and Multidrug Efflux Pump AdeJ from Acinetobacter baumannii. United States. https://doi.org/10.1128/mbio.03732-21
Morgan, Christopher E., Zhang, Zhemin, Bonomo, Robert A., and Yu, Edward W. Tue .
"An Analysis of the Novel Fluorocycline TP-6076 Bound to Both the Ribosome and Multidrug Efflux Pump AdeJ from Acinetobacter baumannii". United States. https://doi.org/10.1128/mbio.03732-21. https://www.osti.gov/servlets/purl/1982984.
@article{osti_1982984,
title = {An Analysis of the Novel Fluorocycline TP-6076 Bound to Both the Ribosome and Multidrug Efflux Pump AdeJ from Acinetobacter baumannii},
author = {Morgan, Christopher E. and Zhang, Zhemin and Bonomo, Robert A. and Yu, Edward W.},
abstractNote = {Antibiotic resistance among bacterial pathogens continues to pose a serious global health threat. Multidrug-resistant (MDR) strains of the Gram-negative organism Acinetobacter baumannii utilize a number of resistance determinants to evade current antibiotics. One of the major resistance mechanisms employed by these pathogens is the use of multidrug efflux pumps. These pumps extrude xenobiotics directly out of bacterial cells, resulting in treatment failures when common antibiotics are administered. Here, the structure of the novel tetracycline antibiotic TP-6076, bound to both the Acinetobacter drug efflux pump AdeJ and the ribosome from Acinetobacter baumannii, using single-particle cryo-electron microscopy (cryo-EM), is elucidated. In this work, the structure of the AdeJ–TP-6076 complex is solved, and we show that AdeJ utilizes a network of hydrophobic interactions to recognize this fluorocycline. Concomitant with this, we elucidate three structures of TP-6076 bound to the A. baumannii ribosome and determine that its binding is stabilized largely by electrostatic interactions. We then compare the differences in binding modes between TP-6076 and the related tetracycline antibiotic eravacycline in both targets. These differences suggest that modifications to the tetracycline core may be able to alter AdeJ binding while maintaining interactions with the ribosome. Together, this work highlights how different mechanisms are used to stabilize the binding of tetracycline-based compounds to unique bacterial targets and provides guidance for the future clinical development of tetracycline antibiotics.},
doi = {10.1128/mbio.03732-21},
journal = {mBio (Online)},
number = 1,
volume = 13,
place = {United States},
year = {Tue Feb 01 00:00:00 EST 2022},
month = {Tue Feb 01 00:00:00 EST 2022}
}
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