HC2091 kills Mycobacterium tuberculosis by targeting the MmpL3 mycolic acid transporter [PublishAheadOfPrint]

Tuberculosis, caused by the intracellular pathogen Mycobacterium tuberculosis (Mtb), is a deadly disease that requires a long course of treatment. The emergence of drug resistant strains has driven efforts to discover new small molecules that can kill the bacterium. Here we report characterizations of the compound HC2091 that kills Mtb in a time- and dose-dependent manner in vitro, as well as inhibiting Mtb growth in macrophages. Whole genome sequencing of spontaneous resistant mutants to HC2091 identified single nucleotide variants in the mmpL3 mycolic acid transporter gene. HC2091 resistant mutants do not exhibit cross-resistance with the well-characterized MmpL3 inhibitor SQ109, suggesting a distinct mechanism of interaction with MmpL3. Additionally, HC2091 does not modulate bacterial membrane potential or kill non-replicating Mtb, thus acting differently from other known MmpL3 inhibitors. RNA-seq transcriptional profiling and lipid profiling of Mtb treated with HC2091 or SQ109 show that both compounds target a similar pathway. HC2091 has a dissimilar chemical structure from previously described MmpL3 inhibitors, supporting that HC2091 is a new class of MmpL3 inhibitor.

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