article · Antibiotics
Researchers evaluated the anti-tubercular properties of a triazole-thiol compound and its Schiff bases against standard and multi-drug-resistant strains of Mycobacterium tuberculosis. Using whole-cell assays, the parent compound demonstrated notable inhibitory activity against both the standard H37Rv strain and resistant bacterial strains. Computational docking and molecular dynamics simulations were subsequently applied to evaluate potential cellular targets. This identified beta-ketoacyl acyl carrier protein synthase I, known as KasA, as the primary molecular target. Binding energy calculations indicated that the compound binds more strongly to KasA than the standard inhibitor thiolactomycin. Further structural analysis showed that the compound forms hydrogen bonds with catalytic histidine residues, disrupts helix movement to block fatty-acid substrate access, and induces specific loop changes that close off the binding site to malonyl substrates, explaining its stronger inhibitory performance.
Tuberculosis remains a severe global health threat, particularly due to the rise of strains that are resistant to conventional treatments. Uncovering new small molecules that inhibit critical bacterial enzymes provides valuable pathways for antimicrobial drug design. Identifying how these chemical structures interact with essential bacterial machinery helps scientists target drug-resistant infections more effectively.
This research is at an early discovery stage, providing a lead candidate for pharmaceutical developers and medicinal chemists working on anti-tubercular drug pipelines. The identified compound and its demonstrated mechanism against drug-resistant strains could serve as a starting point for lead optimisation programmes, though it remains far from clinical development and requires extensive downstream testing, formulation, and safety evaluation.
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In the present investigation, the parent compound 4-amino-5-(4-fluoro-3-phenoxyphenyl)-4<i>H</i>-1,2,4-triazole-3-thiol (<b>1</b>) and its Schiff bases <b>2</b>, <b>3</b>, and <b>4</b> were subjected to whole-cell anti-TB against H37Rv and multi-drug-resistant (MDR) strains of <i>Mycobacterium tuberculosis</i> (MTB) by resazurin microtiter assay (REMA) plate method. Test compound <b>1</b> exhibited promising anti-TB activity against H37Rv and MDR strains of MTB at 5.5 µg/mL and 11 µg/mL, respectively. An attempt to identify the suitable molecular target for compound <b>1</b> was performed using a set of triazole thiol cellular targets, including β-ketoacyl carrier protein synthase III (FABH), β-ketoacyl ACP synthase I (KasA), CYP121, dihydrofolate reductase, enoyl-acyl carrier protein reductase, and <i>N</i>-acetylglucosamine-1-phosphate uridyltransferase. MTB β-ketoacyl ACP synthase I (KasA) was identified as the cellular target for the promising anti-TB parent compound <b>1</b> via docking and molecular dynamics simulation. MM(GB/PB)SA binding free energy calculation revealed stronger binding of compound <b>1</b> compared with KasA standard inhibitor thiolactomycin (TLM). The inhibitory mechanism of test compound <b>1</b> involves the formation of hydrogen bonding with the catalytic histidine residues, and it also impedes access of fatty-acid substrates to the active site through interference with α5-α6 helix movement. Test compound <b>1</b>-specific structural changes at the ALA274-ALA281 loop might be the contributing factor underlying the stronger anti-TB effect of compound <b>1</b> when compared with TLM, as it tends to adopt a closed conformation for the access of malonyl substrate to its binding site.
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DOI: 10.3390/antibiotics9090559
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