Targeting Mycobacterium tuberculosis Sensitivity to Thiol Stress at Acidic pH Kills the Bacterium and Potentiates Antibiotics

Cell Chem Biol. 2017 Aug 17;24(8):993-1004.e4. doi: 10.1016/j.chembiol.2017.06.018. Epub 2017 Aug 3.


Mycobacterium tuberculosis (Mtb) must sense and adapt to immune pressures such as acidic pH during pathogenesis. The goal of this study was to isolate compounds that inhibit acidic pH resistance, thus defining virulence pathways that are vulnerable to chemotherapy. Here, we report that the compound AC2P36 selectively kills Mtb at acidic pH and potentiates the bactericidal activity of isoniazid, clofazimine, and diamide. We show that AC2P36 activity is associated with thiol stress and causes an enhanced accumulation of intracellular reactive oxygen species at acidic pH. Mechanism of action studies demonstrate that AC2P36 directly depletes Mtb thiol pools, with enhanced depletion of free thiols at acidic pH. These findings support that Mtb is especially vulnerable to thiol stress at acidic pH and that chemical depletion of thiol pools is a promising target to promote Mtb killing and potentiation of antimicrobials.

Keywords: Mycobacterium tuberculosis; antibiotic potentiation; chemical biology; environmental adaptation; oxidative stress; redox homeostasis; thiol homeostasis.

MeSH terms

  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology*
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism
  • Glutathione / chemistry
  • Hydrogen-Ion Concentration
  • Mycobacterium tuberculosis / drug effects*
  • Mycobacterium tuberculosis / growth & development
  • Oxidative Stress / drug effects
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Reactive Oxygen Species / metabolism
  • Sigma Factor / genetics
  • Sigma Factor / metabolism
  • Structure-Activity Relationship
  • Sulfhydryl Compounds / chemistry
  • Sulfhydryl Compounds / metabolism*
  • Sulfones / chemistry
  • Sulfones / pharmacology*


  • 5-chloro-N-(3-chloro-4-methoxyphenyl)-2-methylsulfonylpyrimidine-4-carboxamide
  • Anti-Bacterial Agents
  • Bacterial Proteins
  • Pyrimidines
  • Reactive Oxygen Species
  • SigH protein, bacteria
  • Sigma Factor
  • Sulfhydryl Compounds
  • Sulfones
  • Glutathione