Abstract
The anti-tuberculosis (TB) agent IMB-T130 was speculated to be a multi-target compound. In this research, we found that IMB-T130 inhibits the catalytic activity of Mycobacterium tuberculosis 3-dehydroquinate synthase (MtDHQS), the enzyme in the second step of the shikimate pathway. IMB-T130 was identified as a selective inhibitor of MtDHQS with an IC50 value of 0.87 μg/mL. The interaction between the compound and protein was analysed by surface plasmon resonance and circular dichroism. Based on the in silico molecular docking results, the essential amino acids in the binding pocket were then confirmed by site-directed mutagenesis. Overexpression of DHQS reduced the antibacterial activity of IMB-T130 in cells, verifying that DHQS is the target of IMB-T130. IMB-T130 inhibited standard and drug-resistant M. tuberculosis strains by targeting DHQS. Our findings improve our understanding of MtDHQS and make it to be a potential target for new anti-TB drug discovery.
Highlights
Tuberculosis (TB), a serious infectious disease caused by Mycobacterium tuberculosis, is a major threat to global human health
We found that IMB-T130 strongly inhibited dehydroquinate synthase (DHQS) in vitro (Fig. 1), and that DHQS may play an important role in the antibacterial effect of IMB-T130
DHQS catalyses the second step of the shikimate pathway, which is conserved among various bacterial species[9,24]
Summary
Tuberculosis (TB), a serious infectious disease caused by Mycobacterium tuberculosis, is a major threat to global human health. The essential role of the shikimic acid pathway in these organisms has been confirmed by site-directed mutagenesis, where the growth of mutant strains was inhibited in the absence of exogenous aromatic supplements[7]. The absence of this pathway in mammals makes it an attractive target for developing new antibiotics with low toxicity toward humans[4]. M. tuberculosis 3-dehydroquinate synthase (DHQS), which is encoded by the aroB gene (Rv2538c), catalyses the second step of the shikimate pathway It catalyses the conversion of 3-deoxy-D-Darabino-heptulosonate 7-phosphate (DAHP) to 3-dehydroquinate (DHQ)[8,9].
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