{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,4]],"date-time":"2026-04-04T13:21:04Z","timestamp":1775308864218,"version":"3.50.1"},"reference-count":80,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2022,9,20]],"date-time":"2022-09-20T00:00:00Z","timestamp":1663632000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Bangalore Bioinnovation Centre, Karnataka Innovation and Technology Society, Department of Electronics, IT, BT and S&amp;T, Government of Karnataka, India"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The World Health Organization has put drug resistance in tuberculosis on its list of significant threats, with a critical emphasis on resolving the genetic differences in Mycobacterium tuberculosis. This provides an opportunity for a better understanding of the evolutionary progression leading to anti-microbial resistance. Anti-microbial resistance has a great impact on the economic stability of the global healthcare sector. We performed a timeline genomic analysis from 2003 to 2021 of 578 mycobacterium genomes to understand the pattern underlying genomic variations. Potential drug targets based on functional annotation was subjected to pharmacophore-based screening of FDA-approved phyto-actives. Reaction search, MD simulations, and metadynamics studies were performed. A total of 4,76,063 mutations with a transition\/transversion ratio of 0.448 was observed. The top 10 proteins with the least number of mutations were high-confidence drug targets. Aminoglycoside 2\u2032-N-acetyltransferase protein (AAC2\u2032), conferring resistance to aminoglycosides, was shortlisted as a potential drug target based on its function and role in bait drug synergism. Gentamicin-AAC2\u2032 binding pose was used as a pharmacophore template to screen 10,570 phyto-actives. A total of 66 potential hits were docked to obtain naloxone as a lead\u2014active with a docking score of \u22126.317. Naloxone is an FDA-approved drug that rapidly reverses opioid overdose. This is a classic case of a repurposed phyto-active. Naloxone consists of an amine group, but the addition of the acetyl group is unfavorable, with a reaction energy of 612.248 kcal\/mol. With gentamicin as a positive control, molecular dynamic simulation studies were performed for 200 ns to check the stability of binding. Metadynamics-based studies were carried out to compare unbinding energy with gentamicin. The unbinding energies were found to be \u221268 and \u221274 kcal\/mol for naloxone and gentamycin, respectively. This study identifies naloxone as a potential drug candidate for a bait drug synergistic approach against Mycobacterium tuberculosis.<\/jats:p>","DOI":"10.3390\/molecules27196150","type":"journal-article","created":{"date-parts":[[2022,9,20]],"date-time":"2022-09-20T22:36:44Z","timestamp":1663713404000},"page":"6150","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Mycobacterium Time-Series Genome Analysis Identifies AAC2\u2032 as a Potential Drug Target with Naloxone Showing Potential Bait Drug Synergism"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9187-7753","authenticated-orcid":false,"given":"Vidya","family":"Niranjan","sequence":"first","affiliation":[{"name":"Department of Biotechnology, R. V. College of Engineering, Mysuru Road, Kengeri, Bangalore 560059, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9326-1426","authenticated-orcid":false,"given":"Akshay","family":"Uttarkar","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, R. V. College of Engineering, Mysuru Road, Kengeri, Bangalore 560059, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keerthana","family":"Murali","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, R. V. College of Engineering, Mysuru Road, Kengeri, Bangalore 560059, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Swarna","family":"Niranjan","sequence":"additional","affiliation":[{"name":"Department of Artificial Intelligence and Machine Learning, R. V. College of Engineering, Mysuru Road, Kengeri, Bangalore 560059, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jayalatha","family":"Gopal","sequence":"additional","affiliation":[{"name":"Department of Mathematics, R. V. College of Engineering, Mysuru Road, Kengeri, Bangalore 560059, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jitendra","family":"Kumar","sequence":"additional","affiliation":[{"name":"Bangalore Bioinnovation Centre, Helix Biotech Park, Electronic City Phase 1, Bangalore 560100, India"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1056\/NEJMra1205429","article-title":"Tuberculosis, Drug Resistance, and the History of Modern Medicine","volume":"367","author":"Keshavjee","year":"2012","journal-title":"N. Engl. J. 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