PT  - JOURNAL ARTICLE
AU  - Garry B. Coulson
AU  - Benjamin K. Johnson
AU  - Christopher J. Colvin
AU  - Robert J. Fillinger
AU  - Huiqing Zheng
AU  - Elizabeth R. Haiderer
AU  - Neal D. Hammer
AU  - Robert B. Abramovitch
TI  - Acidic pH-dependent depletion of <em>Mycobacterium tuberculosis</em> thiol pools potentiates antibiotics and oxidizing agents
AID  - 10.1101/095448
DP  - 2016 Jan 01
TA  - bioRxiv
PG  - 095448
4099  - http://biorxiv.org/content/early/2016/12/21/095448.short
4100  - http://biorxiv.org/content/early/2016/12/21/095448.full
AB  - Mycobacterium tuberculosis (Mtb) must sense and adapt to immune pressures such as acidic pH and reactive oxygen species (ROS) 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 acidic pH-dependent compound AC2P36 depletes intracellular thiol pools, sensitizes Mtb to killing by acidic pH, and potentiates the bactericidal activity of isoniazid, clofazimine, and oxidizing agents. We show that the pHdependent activity of AC2P36 is associated with metabolic stress at acidic pH and a pHdependent accumulation of intracellular ROS. Mechanism of action studies show that AC2P36 directly depletes Mtb thiol pools. These data support a model where chemical depletion of Mtb thiol pools at acidic pH enhances sensitivity to oxidative damage, resulting in bacterial killing and potentiation of antibiotics.