Whole cell screen for inhibitors of pH homeostasis in Mycobacterium tuberculosis.
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.
Department of Microbiology and Immunology, Weill Cornell Medical College, New York, New York, USA.
Crystal M
CM
Darby
Helgi I
HI
Ingólfsson
Xiuju
X
Jiang
Chun
C
Shen
Mingna
M
Sun
Nan
N
Zhao
Kristin
K
Burns
Gang
G
Liu
Sabine
S
Ehrt
J David
JD
Warren
Olaf S
OS
Andersen
Olaf S
OS
Anderson
Steven J
SJ
Brickner
Carl
C
Nathan
D000136:Acid-Base Equilibrium / Q000187:drug effects*; D000818:Animals; D000995:Antitubercular Agents / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D002460:Cell Line; D057166:High-Throughput Screening Assays / Q000379:methods; D006706:Homeostasis / Q000187:drug effects*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008564:Membrane Potentials / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000378:metabolism; D014709:Vero Cells
D000995:Antitubercular Agents