Whole Cell Screen for Inhibitors of pH Homeostasis in <i>Mycobacterium tuberculosis</i>

<div><p>Bacterial pathogens like <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) encounter acidic microenvironments in the host and must maintain their acid-base homeostasis to survive. A genetic screen identified two <i>Mtb</i> strains that cannot control intrabacterial pH (pH_IB) in an acidic environment; infection with either strain led to severe attenuation in mice. To search for additional proteins that <i>Mtb</i> requires to survive at low pH, we introduced a whole-cell screen for compounds that disrupt pH_IB, 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 <i>Mtb</i> to survive in acidic environments, a setting in which <i>Mtb</i> is resistant to most of the drugs currently used to treat tuberculosis.</p>