Desiccation promotes DNA damage and rifampin resistance in Mycobacterium tuberculosis
9 affiliations
- 1Weill Cornell Medical College, Department of Medicine, Division of Infectious Diseases, New York, NY USA
- 2Cornell University Meinig School of Biomedical Engineering, Ithaca, NY USA
- 3Weill Cornell Medical College, Department of Microbiology and Immunology, New York, NY USA
- 4Present Address: Biotechnology Department, National Institute of Pharmaceutical Education and Research, Sahibzada Ajit Singh Nagar, India
- 5Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ USA
- 6University of North Carolina School of Medicine, Department of Genetics, Chapel Hill, NC USA
- 7Hackensack Meridian School of Medicine, Nutley, NJ USA
- 8Laboratory of Molecular Biophysics, The Rockefeller University, New York, NY USA
- 9Laboratory of Molecular Pathogenesis, The Rockefeller University, New York, NY USA
Abstract
Mycobacterium tuberculosis (Mtb) is an obligate human pathogen that depends on its ability to spread from host to host to survive as a species. Knowledge of traits supporting transmission is lacking. Here, because desiccation occurs during the generation of Mtb-transmitting aerosol droplets, we exposed Mtb mounted atop a filter platform to varying degrees of humidity to characterize its transcriptomic and metabolomic responses to desiccation and rehydration. Desiccation increased levels of oxidative stress, oxidative damage and double-stranded DNA breaks, activating DNA repair responses required for survival. Expression of the transcription-coupled repair factor, mfd, also increased but this buffered the fitness cost of specific resistance-conferring mutations in rpoB, the target of the frontline drug rifampin. Silencing mfd during aerosolization specifically impaired survival of strains harbouring the most common rifampin resistance allele, S450L. This function is epidemiologically supported by whole-genome sequence analysis of 51,229 clinically circulating strains. These studies suggest that transmission-associated desiccation-induced DNA damage is a potential source of genetic diversification that can potentiate antibiotic resistance.
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BibTeX
@article{brown2026desiccation,
title = {{Desiccation promotes DNA damage and rifampin resistance in Mycobacterium tuberculosis}},
author = {Christopher D. Brown and Brendon M. Lee and Hannah M. Liu and Amy M. Wu and Andrea Tellez and Harry Zou and Prabhat Ranjan Singh and Kohta Saito and Saurabh Mishra and Megan Brown and Anas Saleh and Narineh M. Odjourian and Melissa Cristaldo and Mingyu Gan and Qingyun Liu and Martin Gengenbacher and Seth A. Darst and Elizabeth A. Campbell and Carl Nathan and Kyu Y. Rhee},
journal = {Nature Microbiology},
year = {2026},
month = aug,
doi = {10.1038/s41564-026-02437-w},
url = {https://doi.org/10.1038/s41564-026-02437-w},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Desiccation promotes DNA damage and rifampin resistance in Mycobacterium tuberculosis
AU - Christopher D. Brown
AU - Brendon M. Lee
AU - Hannah M. Liu
AU - Amy M. Wu
AU - Andrea Tellez
AU - Harry Zou
AU - Prabhat Ranjan Singh
AU - Kohta Saito
AU - Saurabh Mishra
AU - Megan Brown
AU - Anas Saleh
AU - Narineh M. Odjourian
AU - Melissa Cristaldo
AU - Mingyu Gan
AU - Qingyun Liu
AU - Martin Gengenbacher
AU - Seth A. Darst
AU - Elizabeth A. Campbell
AU - Carl Nathan
AU - Kyu Y. Rhee
PY - 2026
DA - 2026/08/26
JO - Nature Microbiology
DO - 10.1038/s41564-026-02437-w
UR - https://doi.org/10.1038/s41564-026-02437-w
AB - Mycobacterium tuberculosis (Mtb) is an obligate human pathogen that depends on its ability to spread from host to host to survive as a species. Knowledge of traits supporting transmission is lacking. Here, because desiccation occurs during the generation of Mtb-transmitting aerosol droplets, we exposed Mtb mounted atop a filter platform to varying degrees of humidity to characterize its transcriptomic and metabolomic responses to desiccation and rehydration. Desiccation increased levels of oxidative stress, oxidative damage and double-stranded DNA breaks, activating DNA repair responses required for survival. Expression of the transcription-coupled repair factor, mfd, also increased but this buffered the fitness cost of specific resistance-conferring mutations in rpoB, the target of the frontline drug rifampin. Silencing mfd during aerosolization specifically impaired survival of strains harbouring the most common rifampin resistance allele, S450L. This function is epidemiologically supported by whole-genome sequence analysis of 51,229 clinically circulating strains. These studies suggest that transmission-associated desiccation-induced DNA damage is a potential source of genetic diversification that can potentiate antibiotic resistance.
SN - 2058-5276
ER -