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Analysis of the Lipid Composition of Mycobacteria by Thin Layer Chromatography
Published on: April 16, 2021
Cell envelope maintenance by PhoP is essential for Mycobacterium tuberculosis methylglyoxal resistance
Phuong M Tran1, Andrea Anaya-Sanchez2, Daisy X Ji1
1Department of Microbiology, NYU Grossman School of Medicine, New York, NY 10016.
Abstract:
During Mycobacterium tuberculosis infections bacteria are engulfed by macrophages, a main line of defense against invading pathogens. Upon activation, macrophages increase glycolysis, producing the antibacterial aldehyde methylglyoxal. To test whether bacterial methylglyoxal resistance is required for robust infections, we sought to identify M. tuberculosis defense mechanisms against methylglyoxal. We identified phoP mutants were among the most highly sensitive strains to methylglyoxal in vitro. phoP mutants are highly attenuated in mice but a phoP mutant was even more attenuated in mice that accumulate methylglyoxal. We further found phoP bacilli were more permeable to methylglyoxal and accumulated glycated proteins. Suppressor mutations in the fatty acid β-oxidation genes fadE25 or fixB restored impermeability and resistance to methylglyoxal to a phoP mutant. Together, our data show that an important role for PhoP is to provide M. tuberculosis resistance to methylglyoxal toxicity in vivo by regulating cell envelope integrity.
Insights
Mycobacterium tuberculosis requires PhoP for resistance to the antibacterial aldehyde methylglyoxal. PhoP regulates cell envelope integrity, crucial for preventing methylglyoxal toxicity during infection.
Area of Science:
- Microbiology
- Immunology
- Biochemistry
Background:
- Macrophages engulf Mycobacterium tuberculosis during infection.
- Activated macrophages produce the antibacterial aldehyde methylglyoxal.
- Bacterial resistance to methylglyoxal may be crucial for infection.
Purpose of the Study:
- Identify Mycobacterium tuberculosis defense mechanisms against methylglyoxal.
- Determine if bacterial methylglyoxal resistance is essential for robust infections.
Main Methods:
- Screened Mycobacterium tuberculosis mutants for methylglyoxal sensitivity.
- Assessed mutant attenuation in a mouse model.
- Analyzed bacterial permeability and protein glycation.
Main Results:
- phoP mutants showed high sensitivity to methylglyoxal in vitro.
- phoP mutants were significantly attenuated in mice, especially those with high methylglyoxal levels.
- phoP mutants exhibited increased methylglyoxal permeability and protein glycation.
- Suppressor mutations in fadE25 or fixB restored resistance.
Conclusions:
- PhoP is essential for Mycobacterium tuberculosis resistance to methylglyoxal toxicity in vivo.
- PhoP regulates cell envelope integrity to control methylglyoxal permeability.
- Fatty acid β-oxidation genes can influence methylglyoxal resistance.
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