3- O-Methyl-Alkylgallates Inhibit Fatty Acid Desaturation in Mycobacterium tuberculosis

Antimicrob Agents Chemother. 2019 Aug 23;63(9):e00136-19. doi: 10.1128/AAC.00136-19. Print 2019 Sep.

Abstract

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 showed the strongest growth inhibition in vitro against M. tuberculosis, with a MIC of 6.25 μM. Furthermore, the most active compounds (3-O-methyl-butyl-, 3-O-methyl-hexylgallate, and 3-O-methyl-octylgallate) were devoid of cytotoxicity against various human cell lines. Furthermore, 3-O-methyl-butylgallate showed favorable absorption, distribution, metabolism, and excretion (ADME) criteria, with a Papp of 6.2 × 10-6 cm/s, and it did not inhibit P-glycoprotein (P-gp), CYP1A2, CYP2B6 or CYP3A4. Whole-genome sequencing of spontaneous resistant mutants indicated that the compounds target the stearoyl-coenzyme A (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 and that 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.

Keywords: 3-O-methyl-alkylgallate; DesA3; Loranthus micranthus; Mycobacterium tuberculosis; antitubercular; fatty acid desaturation; gallic acid; natural product; oleic acid.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology
  • Antitubercular Agents / chemistry*
  • Antitubercular Agents / pharmacokinetics
  • Antitubercular Agents / pharmacology*
  • Cell Line
  • Cytochrome P-450 Enzyme Inhibitors / chemistry
  • Cytochrome P-450 Enzyme Inhibitors / pharmacology
  • Drug Resistance, Bacterial / drug effects
  • Drug Resistance, Bacterial / genetics
  • Fatty Acids / metabolism
  • Gallic Acid / chemistry*
  • Gallic Acid / pharmacology
  • Humans
  • Loranthaceae / chemistry
  • Microbial Sensitivity Tests
  • Mycobacterium tuberculosis / drug effects*
  • Mycobacterium tuberculosis / genetics
  • Mycobacterium tuberculosis / metabolism*
  • Oleic Acid / biosynthesis
  • Oleic Acid / pharmacology
  • Stearoyl-CoA Desaturase / metabolism
  • Structure-Activity Relationship

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Anti-Bacterial Agents
  • Antitubercular Agents
  • Cytochrome P-450 Enzyme Inhibitors
  • Fatty Acids
  • Oleic Acid
  • Gallic Acid
  • Stearoyl-CoA Desaturase