{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T07:48:50Z","timestamp":1773215330927,"version":"3.50.1"},"reference-count":105,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T00:00:00Z","timestamp":1773100800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The rapid spread of antibiotic resistance through plasmid-mediated conjugation remains a primary global health concern. Despite its critical role in horizontal gene transfer, no approved drugs currently target this process, leaving a critical therapeutic gap. Integration Host Factor (IHF), a DNA-binding protein essential for plasmid replication and mobilization, emerges as a promising yet underexplored target for anti-conjugation strategies. This work aimed to develop a predictive computational model and identify small molecules that disrupt IHF function, thereby reducing plasmid transfer and limiting resistance gene dissemination. A curated dataset of 65 compounds with reported anti-plasmid activity was analyzed using a 3D-QSAR model based on algebraic descriptors computed with QuBiLS-MIDAS. The model was validated through leave-one-out cross-validation (Q2 = 0.82), Tropsha\u2019s criteria, and Y-scrambling. Representative compounds were selected via pharmacophore clustering and evaluated through molecular docking at both the DNA-binding site and a predicted allosteric pocket of IHF. The most promising complexes underwent 200 ns molecular dynamics simulations to assess stability and interaction patterns. The QSAR model demonstrated strong predictive performance (R2 = 0.90). Docking simulations revealed more favorable binding energies at the allosteric site (up to \u221212.15 kcal\/mol) compared to the DNA-binding site. Molecular dynamics confirmed the stability of these interactions, with allosteric complexes showing lower RMSD fluctuations and consistent binding energy profiles. Dynamic cross-correlation analysis revealed that allosteric ligand binding induces conformational changes in key catalytic residues, including Pro65, Pro61, and Leu66. These alterations may compromise DNA recognition and disrupt the initiation of replication. To our knowledge, this is the first computational study proposing allosteric inhibition of IHF as an anti-conjugation strategy. These findings provide a foundation for experimental validation and the development of novel agents to prevent horizontal gene transfer, offering a promising approach to restoring antibiotic efficacy against multidrug-resistant pathogens.<\/jats:p>","DOI":"10.3390\/ijms27062526","type":"journal-article","created":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T09:55:38Z","timestamp":1773136538000},"page":"2526","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Computational Identification of Potential Novel Allosteric IHF Inhibitors Using QSAR Modeling to Inhibit Plasmid-Mediated Antibiotic Resistance"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-4454-3126","authenticated-orcid":false,"given":"Oscar","family":"Saurith-Coronell","sequence":"first","affiliation":[{"name":"Departamento de Medicina, Divisi\u00f3n Ciencias de la Salud, Universidad del Norte, Km 5, V\u00eda Puerto Colombia, Puerto Colombia 081007, Colombia"},{"name":"Grupo de Investigaciones en Qu\u00edmica y Biolog\u00eda, Departamento de Qu\u00edmica y Biolog\u00eda, Facultad de Ciencias B\u00e1sicas, Universidad del Norte, Carrera 51B, Km 5, V\u00eda Puerto Colombia, Barranquilla 081007, Colombia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-8239-5890","authenticated-orcid":false,"given":"Olimpo","family":"Sierra-Hernandez","sequence":"additional","affiliation":[{"name":"Departamento de Medicina, Divisi\u00f3n Ciencias de la Salud, Universidad del Norte, Km 5, V\u00eda Puerto Colombia, Puerto Colombia 081007, Colombia"},{"name":"Grupo de Investigaciones en Qu\u00edmica y Biolog\u00eda, Departamento de Qu\u00edmica y Biolog\u00eda, Facultad de Ciencias B\u00e1sicas, Universidad del Norte, Carrera 51B, Km 5, V\u00eda Puerto Colombia, Barranquilla 081007, Colombia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5247-867X","authenticated-orcid":false,"given":"Juan David","family":"Rodr\u00edguez-Mac\u00edas","sequence":"additional","affiliation":[{"name":"Facultad de Ciencias de la Salud, Exactas y Naturales, Universidad Libre, Barranquilla 080001, Colombia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6128-9504","authenticated-orcid":false,"given":"Jos\u00e9 R.","family":"Mora","sequence":"additional","affiliation":[{"name":"Grupo de Qu\u00edmica Computacional y Te\u00f3rica (QCT-USFQ), Departamento de Ingenier\u00eda Qu\u00edmica, Universidad San Francisco de Quito, Diego de Robles y V\u00eda Interoce\u00e1nica, Quito 170901, Ecuador"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3166-745X","authenticated-orcid":false,"given":"Noel","family":"Perez-Perez","sequence":"additional","affiliation":[{"name":"Colegio de Ciencias e Ingenier\u00edas \u201cEl Polit\u00e9cnico\u201d, Universidad San Francisco de Quito USFQ, Quito 170157, Ecuador"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6300-6923","authenticated-orcid":false,"given":"Jackson J.","family":"Alc\u00e1zar","sequence":"additional","affiliation":[{"name":"Centro de Qu\u00edmica M\u00e9dica, Facultad de Medicina Cl\u00ednica Alemana, Universidad del Desarrollo, Santiago 7780272, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1590-3750","authenticated-orcid":false,"given":"Ricardo Olimpio de","family":"Moura","sequence":"additional","affiliation":[{"name":"Programa de P\u00f3s-Gradua\u00e7\u00e3o em Ci\u00eancias Farmac\u00eauticas (PPGCF), Universidade Estadual da Para\u00edba (UEPB), Campina Grande 58429-500, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2664-4336","authenticated-orcid":false,"given":"Igor Jos\u00e9 dos Santos","family":"Nascimento","sequence":"additional","affiliation":[{"name":"Programa de P\u00f3s-Gradua\u00e7\u00e3o em Ci\u00eancias Farmac\u00eauticas (PPGCF), Universidade Estadual da Para\u00edba (UEPB), Campina Grande 58429-500, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7503-1528","authenticated-orcid":false,"given":"Edgar A.","family":"M\u00e1rquez Braz\u00f3n","sequence":"additional","affiliation":[{"name":"Grupo de Investigaciones en Qu\u00edmica y Biolog\u00eda, Departamento de Qu\u00edmica y Biolog\u00eda, Facultad de Ciencias B\u00e1sicas, Universidad del Norte, Carrera 51B, Km 5, V\u00eda Puerto Colombia, Barranquilla 081007, Colombia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2721-1142","authenticated-orcid":false,"given":"Yovani","family":"Marrero-Ponce","sequence":"additional","affiliation":[{"name":"Facultad de Ingenier\u00eda, Universidad Panamericana, Ciudad de M\u00e9xico 03920, Mexico"},{"name":"Grupo de Medicina Molecular y Traslacional (MeM&T), Colegio de Ciencias de la Salud (COCSA), Escuela de Medicina, Universidad San Francisco de Quito (USFQ), Quito 170157, Ecuador"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1016\/j.chom.2024.05.015","article-title":"Antibiotic Resistance: A Key Microbial Survival Mechanism That Threatens Public Health","volume":"32","author":"Abbas","year":"2024","journal-title":"Cell Host 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