Fluorogenic Probes of the Mycobacterial Membrane as Reporters of Antibiotic Action
Name
nihms-2038171.pdf
Description
Accepted version
Size
2.09 MB
Format
Adobe PDF
Checksum (MD5)
ea233c5f09307663149206600775a564
Author(s)
Wuo, Michael G
Dulberger, Charles L
Warner, Theodore C
Brown, Robert A
Sturm, Alexander
Ultee, Eveline
Bloom-Ackermann, Zohar
Choi, Catherine
Zhu, Junhao
Garner, Ethan C
Date Issued
July 3, 2024
Journal
Journal of the American Chemical Society
Publisher
American Chemical Society
Citation
Michael G. Wuo, Charles L. Dulberger, Theodore C. Warner, Robert A. Brown, Alexander Sturm, Eveline Ultee, Zohar Bloom-Ackermann, Catherine Choi, Junhao Zhu, Ethan C. Garner, Ariane Briegel, Deborah T. Hung, Eric J. Rubin, Laura L. Kiessling; Fluorogenic Probes of the Mycobacterial Membrane as Reporters of Antibiotic Action. Journal American Chemical Society 3 July 2024; 146 (26): 17669–17678.
Version
Author's final manuscript
Abstract
The genus Mycobacterium includes species such as Mycobacterium tuberculosis, which can cause deadly human diseases. These bacteria have a protective cell envelope that can be remodeled to facilitate their survival in challenging conditions. Understanding how such conditions affect membrane remodeling can facilitate antibiotic discovery and treatment. To this end, we describe an optimized fluorogenic probe, N-QTF, that reports on mycolyltransferase activity, which is vital for cell division and remodeling. N-QTF is a glycolipid probe that can reveal dynamic changes in the mycobacterial cell envelope in both fast- and slow-growing mycobacterial species. Using this probe to monitor the consequences of antibiotic treatment uncovered distinct cellular phenotypes. Even antibiotics that do not directly inhibit cell envelope biosynthesis cause conspicuous phenotypes. For instance, mycobacteria exposed to the RNA polymerase inhibitor rifampicin release fluorescent extracellular vesicles (EVs). While all mycobacteria release EVs, fluorescent EVs were detected only in the presence of RIF, indicating that exposure to the drug alters EV content. Macrophages exposed to the EVs derived from RIF-treated cells released lower levels of cytokines, suggesting the EVs moderate immune responses. These data suggest that antibiotics can alter EV content to impact immunity. Our ability to see such changes in EV constituents directly results from exploiting these chemical probes.
MIT Department
Massachusetts Institute of Technology. Department of Chemistry
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DOI of Published Version
https://doi.org/10.1021/jacs.4c00617
