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The continued emergence of multidrug-resistant strains highlights the urgent need for new therapeutic agents with novel mechanisms of action. Here, we report the discovery and comprehensive characterization of DL25, a synthetic desloratadine-derived small molecule exhibiting potent antimycobacterial activity (minimum inhibitory concentration (MIC) 2\u20134 \u03bcg\/mL against multiple mycobacterial species). Using a supra-inhibitory DL25 selection strategy, we isolated and characterized spontaneous resistant mutants. Whole-genome sequencing identified recurrent mutations in aroB, which encodes 3-dehydroquinate synthase (DHQS), an essential enzyme of the shikimate pathway. Consistent with target involvement, aroB overexpression reduced susceptibility to DL25, while DL25 decreased DHQS-associated biochemical activity in vitro with an apparent IC50 of approximately 5.0 \u03bcg\/mL. In addition, DL25 exhibited concentration- and time-dependent bactericidal activity and showed partial synergy with several established antitubercular agents. Structural modeling, molecular docking, and 100 ns molecular dynamics simulations supported stable binding of DL25 within the DHQS active site and identified interactions with residues implicated in substrate recognition and catalysis. Collectively, the genetic, biochemical, and computational findings support DHQS as a biologically relevant target associated with DL25 activity and establish DL25 as a promising lead-like scaffold for the development of future shikimate pathway-directed antimycobacterial agents. More broadly, this study demonstrates the value of integrating genetic, biochemical, and computational approaches for mechanism-guided antituberculosis drug discovery.<\/jats:p>","DOI":"10.1021\/acs.jcim.6c00496","type":"journal-article","created":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T19:55:17Z","timestamp":1784058917000},"page":"8423-8438","source":"Crossref","is-referenced-by-count":0,"title":["Discovery and Mechanism\nof Action of a Novel Desloratadine\nDerivative Inhibiting\n                    <i>Mycobacterium tuberculosis<\/i>\n                    3-Dehydroquinate Synthase"],"prefix":"10.1021","volume":"66","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-3255-5118","authenticated-orcid":true,"given":"Aweke Mulu","family":"Belachew","sequence":"first","affiliation":[{"name":"Chinese Academy of Sciences , , ,","place":["Guangzhou, China, 510530"]},{"name":"University of Chinese Academy of Sciences , ,","place":["Beijing, China, 100049"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haizhou","family":"Li","sequence":"additional","affiliation":[{"name":"Guangzhou Medical University , , ,","place":["Guangzhou, China, 510230"]},{"name":"Guangzhou National Laboratory , ,","place":["Guangzhou, China, 510320"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xirong","family":"Tian","sequence":"additional","affiliation":[{"name":"Guangzhou Medical University , , ,","place":["Guangzhou, China, 510230"]},{"name":"Guangzhou National Laboratory , ,","place":["Guangzhou, China, 510320"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyong","family":"Liu","sequence":"additional","affiliation":[{"name":"Chinese Academy of Sciences , , ,","place":["Guangzhou, China, 510530"]},{"name":"Guangzhou Medical University , , ,","place":["Guangzhou, China, 510230"]},{"name":"Guangzhou National Laboratory , ,","place":["Guangzhou, China, 510320"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cuiting","family":"Fang","sequence":"additional","affiliation":[{"name":"Guangzhou Medical University , , ,","place":["Guangzhou, China, 510230"]},{"name":"Guangzhou National Laboratory , ,","place":["Guangzhou, China, 510320"]},{"name":"Guangzhou Chest Hospital , , ,","place":["Guangzhou, China, 510095"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liqiang","family":"Feng","sequence":"additional","affiliation":[{"name":"Chinese Academy of Sciences , , ,","place":["Guangzhou, China, 510530"]},{"name":"University of Chinese Academy of Sciences , ,","place":["Beijing, China, 100049"]},{"name":"Chinese Academy of Sciences , , ,","place":["Guangzhou, China, 510530"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shouping","family":"Liu","sequence":"additional","affiliation":[{"name":"Guangzhou Medical University , , ,","place":["Guangzhou, China, 510230"]},{"name":"Guangzhou National Laboratory , ,","place":["Guangzhou, China, 510320"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Buhari","family":"Yusuf","sequence":"additional","affiliation":[{"name":"Chinese Academy of Sciences , , ,","place":["Guangzhou, China, 510530"]},{"name":"University of Chinese Academy of Sciences , ,","place":["Beijing, China, 100049"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinxing","family":"Hu","sequence":"additional","affiliation":[{"name":"Guangzhou Medical University , , ,","place":["Guangzhou, China, 510230"]},{"name":"Guangzhou Eighth People\u2019s Hospital of Guangzhou Medical University , ,","place":["Guangzhou, China, 510440"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksey A.","family":"Vatlin","sequence":"additional","affiliation":[{"name":"RUDN University , , ,","place":["Moscow, Russia, 117198"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6595-0811","authenticated-orcid":true,"given":"Andrey E.","family":"Shchekotikhin","sequence":"additional","affiliation":[{"name":"RUDN University , , ,","place":["Moscow, Russia, 117198"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuai","family":"Wang","sequence":"additional","affiliation":[{"name":"Chinese Academy of Sciences , , ,","place":["Guangzhou, China, 510530"]},{"name":"University of Chinese Academy of Sciences , ,","place":["Beijing, China, 100049"]},{"name":"Chinese Academy of Sciences , , ,","place":["Guangzhou, China, 510530"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1993-9547","authenticated-orcid":true,"given":"H. M. Adnan","family":"Hameed","sequence":"additional","affiliation":[{"name":"Chinese Academy of Sciences , , ,","place":["Guangzhou, China, 510530"]},{"name":"University of Chinese Academy of Sciences , ,","place":["Beijing, China, 100049"]},{"name":"Chinese Academy of Sciences , , ,","place":["Guangzhou, China, 510530"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuimu","family":"Lin","sequence":"additional","affiliation":[{"name":"Guangzhou Medical University , , ,","place":["Guangzhou, China, 510230"]},{"name":"Guangzhou National Laboratory , ,","place":["Guangzhou, China, 510320"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5647-6014","authenticated-orcid":true,"given":"Tianyu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Chinese Academy of Sciences , , ,","place":["Guangzhou, China, 510530"]},{"name":"University of Chinese Academy of Sciences , ,","place":["Beijing, China, 100049"]},{"name":"Guangzhou Medical University , , ,","place":["Guangzhou, China, 510230"]},{"name":"Guangzhou National Laboratory , ,","place":["Guangzhou, China, 510320"]},{"name":"Guangzhou Chest Hospital , , ,","place":["Guangzhou, China, 510095"]},{"name":"Chinese Academy of Sciences , , ,","place":["Guangzhou, China, 510530"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,7,14]]},"reference":[{"key":"2026072709084770100_cit1","unstructured":"World Health Organization.\n          .  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Care Med."},{"key":"2026072709084770100_cit4","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2018.00114","article-title":"Molecular\ntargets related drug resistance mechanisms\nin MDR-, XDR-, and TDR-Mycobacterium tuberculosis strains","volume":"8","author":"Hameed","year":"2018","journal-title":"Front. Cell. Infect. Microbiol."},{"issue":"2","key":"2026072709084770100_cit5","first-page":"212","article-title":"Understanding the mechanisms\nof drug\nresistance in Mycobacterium tuberculosis","volume":"39","author":"Ghosh","year":"2021","journal-title":"Indian\nJ. Med. Microbiol."},{"issue":"6","key":"2026072709084770100_cit6","doi-asserted-by":"publisher","first-page":"1547","DOI":"10.1111\/jam.14478","article-title":"Recent updates on drug resistance in Mycobacterium tuberculosis","volume":"128","author":"Singh","year":"2020","journal-title":"J. Appl. 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Sci."},{"issue":"1","key":"2026072709084770100_cit12","first-page":"7","article-title":"Antimicrobial resistance\nin a globalized world: current challenges and future perspectives","volume":"1","author":"Aijaz","year":"2023","journal-title":"Int. J. Pharm. Drug Des."},{"issue":"1","key":"2026072709084770100_cit13","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-35701-z","article-title":"IMB-T130 targets\n3-dehydroquinate synthase and inhibits Mycobacterium tuberculosis","volume":"8","author":"Zhu","year":"2018","journal-title":"Sci. Rep."},{"key":"2026072709084770100_cit14","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2021.692986","article-title":"In vivo inhibition of the 3-dehydroquinate synthase by 7-Deoxysedoheptulose\ndepends on promiscuous uptake by sugar transporters in cyanobacteria","volume":"12","author":"Rapp","year":"2021","journal-title":"Front. 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Cheminf."},{"issue":"1","key":"2026072709084770100_cit18","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0029774","article-title":"Autoluminescent Mycobacterium tuberculosis for rapid, real-time, non-invasive assessment\nof drug and vaccine efficacy","volume":"7","author":"Zhang","year":"2012","journal-title":"PLoS One"},{"issue":"8","key":"2026072709084770100_cit19","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics16081049","article-title":"Assessment\nof the efficacy of the antihistamine drug rupatadine used alone or\nin combination against mycobacteria","volume":"16","author":"Tian","year":"2024","journal-title":"Pharmaceutics"},{"issue":"2","key":"2026072709084770100_cit20","doi-asserted-by":"publisher","DOI":"10.1016\/j.diagmicrobio.2024.116275","article-title":"Application of BactTiter-Glo ATP\nbioluminescence assay for Mycobacterium tuberculosis detection","volume":"109","author":"Abou Mourad Ferreira","year":"2024","journal-title":"Diagn. Microbiol. Infect. Dis."},{"key":"2026072709084770100_cit21","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1016\/j.ejmech.2018.11.054","article-title":"Design and synthesis\nof novel pyrimidine derivatives as potent antitubercular agents","volume":"163","author":"Liu","year":"2019","journal-title":"Eur. J. Med. Chem."},{"issue":"8","key":"2026072709084770100_cit22","doi-asserted-by":"publisher","first-page":"3779","DOI":"10.3390\/ijms26083779","article-title":"Dual mutations\nin MSMEG_0965 and MSMEG_1380 confer\nhigh-level\nresistance to bortezomib and linezolid by both reducing drug intake\nand increasing efflux in Mycobacterium smegmatis","volume":"26","author":"Zhang","year":"2025","journal-title":"Int. J. Mol. Sci."},{"issue":"11","key":"2026072709084770100_cit23","doi-asserted-by":"publisher","first-page":"1565","DOI":"10.3390\/ph16111565","article-title":"Novel derivatives of\nquinoxaline-2-carboxylic acid 1,4-dioxides as antimycobacterial agents:\nmechanistic studies and therapeutic potential","volume":"16","author":"Frolova","year":"2023","journal-title":"Pharmaceuticals"},{"issue":"16","key":"2026072709084770100_cit24","doi-asserted-by":"publisher","first-page":"2785","DOI":"10.1002\/jcc.21256","article-title":"AutoDock4\nand AutoDockTools4: Automated\ndocking with selective receptor flexibility","volume":"30","author":"Morris","year":"2009","journal-title":"J. Comput. Chem."},{"key":"2026072709084770100_cit25","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.softx.2015.06.001","article-title":"GROMACS: High\nperformance\nmolecular simulations through multi-level parallelism from laptops\nto supercomputers","volume":"1\u20132","author":"Abraham","year":"2015","journal-title":"SoftwareX"},{"issue":"9","key":"2026072709084770100_cit26","doi-asserted-by":"publisher","first-page":"1157","DOI":"10.1002\/jcc.20035","article-title":"Development\nand testing of a general amber force field","volume":"25","author":"Wang","year":"2004","journal-title":"J. Comput. Chem."},{"issue":"12","key":"2026072709084770100_cit27","doi-asserted-by":"publisher","first-page":"3144","DOI":"10.1021\/ci300363c","article-title":"Automation of the CHARMM General Force Field (CGenFF)\nI: bond perception and atom typing","volume":"52","author":"Vanommeslaeghe","year":"2012","journal-title":"J. Chem.\nInf. Model."},{"issue":"12","key":"2026072709084770100_cit28","doi-asserted-by":"publisher","first-page":"2577","DOI":"10.1002\/bip.360221211","article-title":"Dictionary of protein secondary structure: pattern\nrecognition of hydrogen-bonded and geometrical features","volume":"22","author":"Kabsch","year":"1983","journal-title":"Biopolymers"},{"key":"2026072709084770100_cit29","doi-asserted-by":"publisher","first-page":"15","DOI":"10.2217\/fmb-2022-0085","article-title":"Antimicrobial\nand antibiofilm activities of desloratadine against multidrug-resistant Acinetobacter baumannii","volume":"18","author":"Eduvirgem","year":"2023","journal-title":"Future Microbiol."},{"key":"2026072709084770100_cit30","doi-asserted-by":"publisher","DOI":"10.1016\/j.medidd.2022.100140","article-title":"Current\nstatus of antihistamines repurposing for infectious diseases","volume":"15","author":"Travi","year":"2022","journal-title":"Med. Drug Discovery"},{"issue":"6","key":"2026072709084770100_cit31","doi-asserted-by":"publisher","first-page":"1239","DOI":"10.1111\/j.1476-5381.2010.01127.x","article-title":"Principles of early\ndrug discovery","volume":"162","author":"Hughes","year":"2011","journal-title":"Br. J. Pharmacol."},{"issue":"11","key":"2026072709084770100_cit32","doi-asserted-by":"publisher","first-page":"751","DOI":"10.1038\/nrd4683","article-title":"Hit and lead criteria\nin drug discovery for infectious diseases of the developing world","volume":"14","author":"Katsuno","year":"2015","journal-title":"Nat. Rev. Drug Discovery"},{"issue":"5707","key":"2026072709084770100_cit33","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1126\/science.1106753","article-title":"A diarylquinoline drug\nactive on the ATP synthase of Mycobacterium tuberculosis","volume":"307","author":"Andries","year":"2005","journal-title":"Science"},{"issue":"11","key":"2026072709084770100_cit34","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0007778","article-title":"Genome\nanalysis of multi- and extensively drug-resistant tuberculosis from\nKwaZulu-Natal, South Africa","volume":"4","author":"Ioerger","year":"2009","journal-title":"PLoS One"},{"issue":"1","key":"2026072709084770100_cit35","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1046\/j.1365-2958.2003.03425.x","article-title":"Genes required for mycobacterial\ngrowth defined by high density mutagenesis","volume":"48","author":"Sassetti","year":"2003","journal-title":"Mol. Microbiol."},{"issue":"4","key":"2026072709084770100_cit36","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1038\/nrg3351","article-title":"Understanding, predicting\nand manipulating the genotypic\nevolution of antibiotic resistance","volume":"14","author":"Palmer","year":"2013","journal-title":"Nat. Rev.\nGenet."},{"issue":"6","key":"2026072709084770100_cit37","doi-asserted-by":"publisher","first-page":"3185","DOI":"10.1073\/pnas.1919390117","article-title":"Antibiotic resistance\nby high-level intrinsic suppression of a frameshift mutation in an\nessential gene","volume":"117","author":"Huseby","year":"2020","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"issue":"3","key":"2026072709084770100_cit38","doi-asserted-by":"publisher","first-page":"1022","DOI":"10.1128\/AAC.01611-09","article-title":"Rates and mechanisms of resistance development in Mycobacterium tuberculosis to a novel diarylquinoline ATP\nsynthase inhibitor","volume":"54","author":"Huitric","year":"2010","journal-title":"Antimicrob. 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