Whole cell screen for inhibitors of pH homeostasis in Mycobacterium tuberculosis.

Crystal M Darby, Helgi I Ingólfsson, Xiuju Jiang, Chun Shen, Mingna Sun, Nan Zhao, Kristin Burns, Gang Liu, Sabine Ehrt, J David Warren, Olaf S Andersen, Olaf S Anderson, Steven J Brickner, Carl Nathan

Index: PLoS ONE 8 , e68942, (2013)

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Abstract

Bacterial pathogens like Mycobacterium tuberculosis (Mtb) encounter acidic microenvironments in the host and must maintain their acid-base homeostasis to survive. A genetic screen identified two Mtb strains that cannot control intrabacterial pH (pHIB) in an acidic environment; infection with either strain led to severe attenuation in mice. To search for additional proteins that Mtb requires to survive at low pH, we introduced a whole-cell screen for compounds that disrupt pHIB, along with counter-screens that identify ionophores and membrane perturbors. Application of these methods to a natural product library identified four compounds of interest, one of which may inhibit novel pathway(s). This approach yields compounds that may lead to the identification of pathways that allow Mtb to survive in acidic environments, a setting in which Mtb is resistant to most of the drugs currently used to treat tuberculosis.