Herbal Drug Candidate as DNA Gyrase Inhibitor in M. Tuberculosis (Causative Agent of Tuberculosis)

Tuberculosis (TB) remains a global health emergency according to WHO, with Sistan and Baluchistan province showing concerning rates, probably related to its long border with Pakistan and Afghanistan, where the CAS family of TB bacteria is prevalent. TB, caused by Mycobacterium tuberculosis, primarily affects the lungs. Some recent studies indicate that natural compounds may offer promising treatment options. This research aims to use computational tools to analyze drug resistance probability in the most studied CAS strain (CAS/NITR۲۰۴) and identify a potential herbal drug candidate that inhibits bacterial DNA gyrase, an essential enzyme for DNA replication, comparing it with moxifloxacin, a known synthetic antibiotic against the bacterial DNA gyrase. The study first compared protein sequences from H۳۷Rv and CAS/NITR۲۰۴ strains, focusing on rpoB, inhA, katG, pncA, gyrA, and gyrB from UniProt and NCBI databases using Clustal Omega alignment. The ۳D structure of the drug target was prepared using the PDB database. Further investigations assessed drug resistance probability in the CAS/NITR۲۰۴ variant. Molecular docking was performed using Maestro software (Schrödinger LLC) with about ۴۵۰ natural ligands collected from Sistan and Baluchistan medicinal plants. Docking utilized Glide module with extra precision mode, and protein-ligand binding energies were calculated via MM-GBSA, compared to moxifloxacin. Top candidates were visualized in PyMOL (Schrödinger LLC) to analyze their positioning in the enzyme active site. The analyzed proteins showed that GyrA (DNA Gyrase subunit A) had five mutations, including two in the Quinolone Resistance-Determining Regions (QRDR). Although these mutations did not align with known patterns that typically cause resistance, GyrA was identified as the most likely target for further investigation into drug resistance. Additional studies revealed no significant differences in the interaction patterns of moxifloxacin between the CAS/NITR۲۰۴ and H۳۷Rv strains, suggesting that the CAS/NITR۲۰۴ strain has likely not developed antibiotic resistance. Two natural compounds derived from the black myrobalan plant (Terminalia chebula) were identified as the most promising potential inhibitors of DNA gyrase. The first compound, Chebulinic Acid (ZINC۰۰۰۱۶۹۳۵۶۸۹۱), exhibited mean docking and MM-GBSA scores of -۴۸.۱۵ kcal/mol for the H۳۷Rv strain and -۴۲.۹ kcal/mol for the CAS/NITR۲۰۴ strain in chain ۱. The second compound, ۳,۴,۶-tri-O-galloyl-beta-D-glucose (PubChem CID: ۱۴۱۸۸۶۴۱), demonstrated scores of -۳۸.۱۳ kcal/mol for H۳۷Rv and -۳۹.۵۸ kcal/mol for CAS/NITR۲۰۴ in chain ۲. In comparison, moxifloxacin recorded approximately -۲۵.۷ kcal/mol scores for both strains and chains. Both natural compounds showed a stronger binding affinity than moxifloxacin, suggesting that Terminalia chebula could be a viable treatment option for both strains. This study identified a local medicinal plant from Sistan and Baluchistan as a potential treatment for tuberculosis, a disease prevalent in this region. Two compounds derived from the myrobalan plant (Terminalia chebula) exhibited stronger binding affinities to the bacterial DNA gyrase than moxifloxacin. This suggests potential efficacy against the H۳۷Rv and CAS/NITR۲۰۴ strains, although further clinical validation is necessary.

کلیدواژه ها:

Tuberculosis (TB) ، mycobacterium tuberculosis ، CAS/NITR۲۰۴ strain ، DNA gyrase ، herbal medicine ، computational biology