Aurachin RE (1) is a strong antibiotic that
was recently
found to possess 1,4-dihydroxy-2-naphthoate prenyltransferase (MenA)
and bacterial electron transport inhibitory activities. Aurachin RE
is the only molecule in a series of aurachin natural products that
has the chiral center in the alkyl side chain at C9′-position.
To identify selective MenA inhibitors against Mycobacterium
tuberculosis, a series of chiral molecules were designed
based on the structures of previously identified MenA inhibitors and 1. The synthesized molecules were evaluated in in vitro assays,
including MenA enzyme and bacterial growth inhibitory assays. We could
identify novel MenA inhibitors that showed significant increase in
potency of killing nonreplicating M. tuberculosis in the low oxygen recovery assay (LORA) without inhibiting other
Gram-positive bacterial growth even at high concentrations. The MenA
inhibitors reported here are useful new pharmacophores for the development
of selective antimycobacterial agents with strong activity against
nonreplicating M. tuberculosis.
Capuramycin (1) and its analogs are strong translocase I (MurX/MraY) inhibitors. In our SAR studies of capuramycin analogs against M. tuberculosis (Mtb), we observed for the first time that a capuramycin analog, UT-01320 (3) killed non-replicating (dormant) Mtb at low concentrations under low-oxygen conditions, whereas selective MurX inhibitors killed only replicating Mtb under aerobic conditions. Interestingly, 3 did not exhibit MurX enzyme inhibitory activity even at high concentrations, however, 3 inhibited bacterial RNA polymerases with the IC50 values of 100-150 nM range. A new RNA polymerase inhibitor 3 displayed strong synergistic effects with a MurX inhibitor SQ 641 (2), a promising preclinical TB drug.
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