Identification of novel potential antibiotics for tuberculosis by in silico structure-based drug screening

The enoyl-acyl carrier protein reductase of Mycobacterium tuberculosis (MTB) is a key enzyme of the type II fatty acid synthesis system. It is involved in the production of mycolic acid and is a known target for isoniazid, an effective antibiotic for tuberculosis treatment. The increasing prevalence of tuberculosis in many areas of the world, which is associated with the rise of drug-resistant MTB strains, presents a major global health threat. In this study, we attempted to identify novel antibiotics specifically targeting the MTB enoyl-acyl carrier protein reductase. We performed in silico structure-based drug screening using the crystal structure data for the MTB enoyl-acyl carrier protein reductase (PDB code; 2H7I) and a virtual compound library, which includes 152,102 chemicals. By a two-step screening method using DOCK (first screening) and GOLD (second screening), we identified 5 chemical compounds expected to have high binding affinity to the active center of the MTB enoyl-acyl carrier protein reductase. Moreover, we examined the antibiotic effects of these chemical compounds on model bacterial strains by in vitro experiments. We found that a chemical compound, which has a basic skeleton comprised of dibenzofuran, acetoamide, trizol, furyl and methylphenyl groups, completely inhibited the growth of Mycobacterium vanbaalenii and had no toxic effects on enterobacteria and cultured mammalian cells. Therefore, the chemical compound is likely to be useful in the research and development of new antibiotics for tuberculosis.

Graphical abstractA novel, potential antibiotic 2-{[4-(2-furylmethyl)-5-(2-methylphenyl)-4H-1,2,4-triazol-3-yl]thio}-N-(2-methoxydibenzo[b,d]furan-3-yl)acetamide identified by in silico structure-based drug screening.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► We identified 4 novel antibiotics for mycobacteria by in silico structure-based drug screening. ► A chemical compound completely inhibited the growth of mycobacteria. ► It had no toxic effects on enterobacteria and cultured mammalian cells. ► The IC50 of the compound is 5.3 μM, indicating that it is a higher affinity compound than isoniazid. ► Structure analysis data suggested that it is effective for isoniazid-resistant mycobacteria.