Benzene Amide Ether Scaffold is Active against Non-replicating and Intracellular Mycobacterium tuberculosis

New drugs to treat
tuberculosis which target intractable bacterial
populations are required to develop shorter and more effective treatment
regimens. The benzene amide ether scaffold has activity against intracellular Mycobacterium tuberculosis, but low activity against
extracellular, actively replicating M. tuberculosis. We determined that these molecules have bactericidal activity against
non-replicating M. tuberculosis but
not actively replicating bacteria. Exposure to compounds depleted
ATP levels in non-replicating bacteria and increased the oxygen consumption
rate; a subset of molecules led to the accumulation of intrabacterial
reactive oxygen species. A comprehensive screen of M. tuberculosis strains identified a number of under-expressing
strains as more sensitive to compounds under replicating conditions
including QcrA and QcrB hypomorphs. We determined the global gene
expression profile after compound treatment for both replicating and
nutrient-starved M. tuberculosis. We
saw compound-dependent changes in the expression of genes involved
in energy metabolism under both conditions. Taken together, our data
suggest that the scaffold targets respiration in M.
tuberculosis.