Genetic factors affecting storage and utilization of lipids during dormancy in Mycobacterium tuberculosis
Name
sturm-et-al-2024-genetic-factors-affecting-storage-and-utilization-of-lipids-during-dormancy-in-mycobacterium.pdf
Description
Published version
Size
2.06 MB
Format
Adobe PDF
Checksum (MD5)
24aa5a62d77500fe1bb08c940c38bcc1
Author(s)
Sturm, Alexander
Sun, Penny
Avila-Pacheco, Julian
Clatworthy, Anne E
Bloom-Ackermann, Zohar
Wuo, Michael G
Gomez, James E
Jin, Soomin
Clish, Clary B
Kiessling, Laura L
Date Issued
January 18, 2024
Journal
mBio
Publisher
American Society for Microbiology
Citation
Sturm A, Sun P, Avila-Pacheco J, Clatworthy AE, Bloom-Ackermann Z, Wuo MG, Gomez JE, Jin S, Clish CB, Kiessling LL, Hung DT. 2024. Genetic factors affecting storage and utilization of lipids during dormancy in Mycobacterium tuberculosis. mBio 15:e03208-23.
Version
Final published version
Abstract
Mycobacterium tuberculosis (Mtb) can adopt a non-growing dormant state during infection that may be critical to both active and latent tuberculosis. During dormancy, Mtb is widely tolerant toward antibiotics, a significant obstacle in current anti-tubercular drug regimens, and retains the ability to persist in its environment. We aimed to identify novel mechanisms that permit Mtb to survive dormancy in an in vitro carbon starvation model using transposon insertion sequencing and gene expression analysis. We identified a previously uncharacterized component of the lipid transport machinery, omamC, which was upregulated and required for survival during carbon starvation. We show that OmamC plays a role both in increasing fatty acid stores during growth in rich media and enhancing fatty acid utilization during starvation. Besides its involvement in lipid metabolism, OmamC levels affected the expression of the anti-anti-sigma factor rv0516c and other genes to improve Mtb survival during carbon starvation and increase its tolerance toward rifampicin, a first-line drug effective against non-growing Mtb. Importantly, we show that Mtb can be eradicated during carbon starvation, in an OmamC-dependent manner, by inhibiting lipid metabolism with the lipase inhibitor tetrahydrolipstatin. This work casts new light into the survival processes of non-replicating, drug-tolerant Mtb by identifying new proteins involved in lipid metabolism required for the survival of dormant bacteria and exposing a potential vulnerability that could be exploited for antibiotic discovery.
MIT Department
Massachusetts Institute of Technology. Department of Chemistry
Broad Institute of MIT and Harvard
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DOI of Published Version
https://doi.org/10.1128/mbio.03208-23
