Abstract
Mycobacterium abscessus is an emerging pathogen causing lung infection predominantly in patients with underlying structural abnormalities or lung disease and is resistant to most frontline antibiotics. As the pathogenic mechanisms of M. abscessus in the context of the lung are not well-understood, we developed an infection model using air–liquid interface culture and performed a transposon mutagenesis and sequencing screen to identify genes differentially required for bacterial survival in the lung. Biotin cofactor synthesis was required for M. abscessus growth due to increased intracellular biotin demand, while pharmacological inhibition of biotin synthesis prevented bacterial proliferation. Biotin was required for fatty acid remodelling, which increased cell envelope fluidity and promoted M. abscessus survival in the alkaline lung environment. Together, these results indicate that biotin-dependent fatty acid remodelling plays a critical role in pathogenic adaptation to the lung niche, suggesting that biotin synthesis and fatty acid metabolism might provide therapeutic targets for treatment of M. abscessus infection.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 481-497 |
| Number of pages | 17 |
| Journal | Nature Microbiology |
| Volume | 8 |
| Issue number | 3 |
| DOIs | |
| State | Published - Mar 2023 |
Bibliographical note
Funding Information:We thank all members of the Rubin and Fortune labs for input and advice on the manuscript; J.-A. Park and C. Mwase for assistance with air–liquid interface cultures; the Biopolymers Facility at Harvard Medical School for sequencing; and the Microscopy Resources on the North Quad (MicRoN) core at Harvard Medical School for assistance with microscopy. Electron microscopy imaging was performed in the HMS Electron Microscopy Facility. M.R.S. is a Merck Fellow of the Damon Runyon Cancer Research Foundation, DRG-2415-20. E.J.R. was supported by a Dean’s Innovation Award from Harvard Medical School, and by NIH/NIAID under award number R21AI156772. A.M. acknowledges support from the Ludwig Center for Metastasis. D.B.M acknowledges NIH R01 AI049313 and NIH U19 AI162584.
Funding Information:
We thank all members of the Rubin and Fortune labs for input and advice on the manuscript; J.-A. Park and C. Mwase for assistance with air–liquid interface cultures; the Biopolymers Facility at Harvard Medical School for sequencing; and the Microscopy Resources on the North Quad (MicRoN) core at Harvard Medical School for assistance with microscopy. Electron microscopy imaging was performed in the HMS Electron Microscopy Facility. M.R.S. is a Merck Fellow of the Damon Runyon Cancer Research Foundation, DRG-2415-20. E.J.R. was supported by a Dean’s Innovation Award from Harvard Medical School, and by NIH/NIAID under award number R21AI156772. A.M. acknowledges support from the Ludwig Center for Metastasis. D.B.M acknowledges NIH R01 AI049313 and NIH U19 AI162584.
Publisher Copyright:
© 2023, The Author(s), under exclusive licence to Springer Nature Limited.