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

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.

Mycobacterium tuberculosis transcriptional regulator Rv1019 is upregulated in hypoxia, and negatively regulates Rv3230c‐Rv3229c operon encoding enzymes in the oleic acid biosynthetic pathway

“…Oleic acid, an unsaturated 18-carbon fatty acid, is a major precursor of mycobacterial membrane phospholipids. Rv3229c (DesA3) forms a functional complex with the corresponding oxidoreductase Rv3230c and converts saturated stearic acid into unsaturated oleic acid in the presence of molecular oxygen and NADPH [21,25]. Deletion of MSMEG_1886 (desA3) was partially auxotrophic for oleic acid [26].…”

Mycobacterium tuberculosis transcriptional regulator Rv1019 is upregulated in hypoxia and negatively regulates Rv3230c-Rv3229c operon encoding enzymes in the oleic acid biosynthetic pathway

“…Oleic acid, an unsaturated 18-carbon fatty acid, is a major precursor of mycobacterial membrane phospholipids. Rv3229c (DesA3) forms a functional complex with the corresponding oxidoreductase Rv3230c and converts saturated stearic acid into unsaturated oleic acid in the presence of molecular oxygen and NADPH [21] [26].…”

Integrated Multi-omics, Virtual Screening and Molecular Docking Analysis of Methicillin-Resistant Staphylococcus aureus USA300 for the Identification of Potential Therapeutic Targets: An In-Silico Approach

“…Many specific drug targets that are identified from the common metabolic pathways like cysteine desulfurase (Q2FZY5), D-alanine-D-alanineligase (A8Z4Y6), Malonyl CoA-acyl carrier protein transacylase (Q93QD4), Dihydropteroate synthase, Dihydrofolate reductase (Q2G0Q7), Glutamine synthetase (P0A040), ABC transporter, and Penicillin-binding proteins, ribosomal proteins, etc. It is seen that some of these proteins have been targeted in several other pathogenic bacteria to overcome survivability and drug resistance (Giordano et al 2018;Prosser and de Carvalho 2013;Zhang et al 2007;Liu et al 2006;Kumar et al 2018;Rehberg et al 2019;Levy et al 2008;He et al 2020;Cui et al 2019). So, targeting these essential non-host proteins in MRSA USA300 may pave the way to discovering new potential antibacterial therapeutics that can compromise the survivability of the drug-resistant S. aureus.…”