3-O-Methyl-alkylgallates inhibit fatty acid desaturation in Mycobacterium tuberculosis. | Academic Article individual record

In the quest for new antibacterial lead structures, activity screening against Mycobacterium tuberculosis identified antitubercular effects of gallic acid derivatives isolated from the Nigerian mistletoe Loranthus micranthus Structure-activity relationship studies indicated that 3-O-methyl-alkylgallates comprising aliphatic ester chains with four to eight carbon atoms result in strongest growth inhibition in vitro against M. tuberculosis with a minimal inhibitory concentration (MIC) of 6.25 μM. Furthermore, the most active compounds (3-O-methyl-butyl-, 3-O-methyl-hexyl- and 3-O-methyl-octylgallate) were devoid of cytotoxicity against various human cell lines. Furthermore, 3-O-methyl-butylgallate showed favorable ADME criteria with a Papp of 6.2 x 10-6 cm/s, and it did not inhibit P-gp nor CYP1A2, CYP2B6, or CYP3A4. Whole genome sequencing of spontaneous resistant mutants indicated that the compounds target the stearoyl-CoA delta-9 desaturase DesA3 and thereby inhibit oleic acid synthesis. Supplementation assays demonstrated that oleic acid addition to the culture medium antagonizes the inhibitory properties of gallic acid derivatives, while sodium salts of saturated palmitic and stearic acid did not show compensatory effects. The moderate bactericidal effect of 3-O-methyl-butylgallate in monotreatment was synergistically enhanced in combination treatment with isoniazid leading to sterilization in liquid culture.

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Rehberg, N., Omeje, E., Ebada, S. S., van Geelen, L., Liu, Z., Sureechatchayan, P., ... Kalscheuer, R.
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