{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T06:07:39Z","timestamp":1785564459187,"version":"3.56.0"},"reference-count":49,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2024,6,25]],"date-time":"2024-06-25T00:00:00Z","timestamp":1719273600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Typhoid fever, caused by <jats:italic>Salmonella<\/jats:italic> enterica serovar <jats:italic>typhi<\/jats:italic>, presents a substantial global health threat, particularly in regions with limited healthcare infrastructure. The rise of multidrug-resistant strains of <jats:italic>S. typhi<\/jats:italic> exacerbates this challenge, severely compromising conventional treatment efficacy due to over activity of efflux pumps. In our study, a comprehensive exploration of two fundamental aspects to combat MDR in <jats:italic>S. typhi<\/jats:italic> is carried out; i.e. employing advanced bioinformatics analyses and AlphaFold AI, We successfully identified and characterised a putative homologue, ABC-TPA, reminiscent of the P-glycoprotein (P-gp) known for its role in multidrug resistance in diverse pathogens. This discovery provides a critical foundation for understanding the potential mechanisms driving antibiotic resistance in <jats:italic>S. typhi<\/jats:italic>. Furthermore, employing computational methodologies, We meticulously assessed the potential of lignans, specifically Schisandrin A, B, and C, as promising Efflux Pump Inhibitors (EPIs) against the identified P-gp homologue in <jats:italic>S. typhi<\/jats:italic>. Noteworthy findings revealed robust binding interactions of Schisandrin A and B with the target protein, indicating substantial inhibitory capabilities. In contrast, Schisandrin C exhibited instability, showing varied effectiveness among the evaluated lignans. Pharmacokinetics and toxicity predictions underscored the favourable attributes of Schisandrin A, including prolonged action duration. Furthermore, high systemic stability and demanished toxicity profile of SA and SB present their therapeutic efficacy against MDR. This comprehensive investigation not only elucidates potential therapeutic strategies against MDR strains of <jats:italic>S. typhi<\/jats:italic> but also highlights the relevance of computational approaches in identifying and evaluating promising candidates. These findings lay a robust foundation for future empirical studies to address the formidable challenges antibiotic resistance poses in this clinically significant infectious diseases.<\/jats:p>","DOI":"10.1371\/journal.pone.0303285","type":"journal-article","created":{"date-parts":[[2024,6,25]],"date-time":"2024-06-25T18:59:26Z","timestamp":1719341966000},"page":"e0303285","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":5,"title":["Computational evaluation of efflux pump homologues and lignans as potent inhibitors against multidrug-resistant Salmonella typhi"],"prefix":"10.1371","volume":"19","author":[{"given":"Iqra","family":"Shafique","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1084-6782","authenticated-orcid":true,"given":"Mehak","family":"Rafiq","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nosheen Fatima","family":"Rana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Farid","family":"Menaa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatemah","family":"Almalki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alya","family":"Aljuaid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sulaiman Mohammed","family":"Alnasser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amenah S.","family":"Alotaibi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madahiah Bint E.","family":"Masood","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tahreem","family":"Tanweer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,6,25]]},"reference":[{"issue":"1","key":"pone.0303285.ref001","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1038\/s41598-023-27400-1","article-title":"Identification of collaborative cross mouse strains permissive to Salmonella enterica serovar Typhi infection","volume":"13","author":"KR Alugupalli","year":"2023","journal-title":"Scientific Reports"},{"key":"pone.0303285.ref002","doi-asserted-by":"crossref","first-page":"129928","DOI":"10.1016\/j.molstruc.2021.129928","article-title":"A review of the nanomaterials use for the diagnosis and therapy of salmonella typhi","volume":"1230","author":"R Arshad","year":"2021","journal-title":"Journal of Molecular Structure"},{"key":"pone.0303285.ref003","volume-title":"StatPearls","author":"JV Ashurst","year":"2019"},{"issue":"1","key":"pone.0303285.ref004","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1097\/MOG.0000000000000406","article-title":"The evolution of antimicrobial resistance in Salmonella Typhi","volume":"34","author":"A Karkey","year":"2018","journal-title":"Current Opinion in Gastroenterology"},{"key":"pone.0303285.ref005","doi-asserted-by":"crossref","first-page":"794868","DOI":"10.3389\/fpubh.2021.794868","article-title":"Rising XDR-typhoid fever cases in Pakistan: are we heading back to the pre-antibiotic era?","volume":"9","author":"MH Butt","year":"2022","journal-title":"Frontiers in Public Health"},{"issue":"9","key":"pone.0303285.ref006","doi-asserted-by":"crossref","first-page":"1544","DOI":"10.3923\/pjbs.2007.1544.1546","article-title":"Antibacterial effects of water soluble green tea extracts on multi-antibiotic resistant isolates of Pseudomonas aeruginosa","volume":"10","author":"NH Jazani","year":"2007","journal-title":"Pakistan Journal of Biological Sciences: PJBS"},{"key":"pone.0303285.ref007","doi-asserted-by":"crossref","first-page":"120391","DOI":"10.1016\/j.lfs.2022.120391","article-title":"Microbial resistance: The role of efflux pump superfamilies and their respective substrates","volume":"295","author":"\u00cdR Garcia","year":"2022","journal-title":"Life Sciences"},{"issue":"12","key":"pone.0303285.ref008","doi-asserted-by":"crossref","first-page":"2484","DOI":"10.3390\/microorganisms9122484","article-title":"Emerging trends of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Salmonella Typhi in a tertiary care Hospital of Lahore, Pakistan","volume":"9","author":"M Zakir","year":"2021","journal-title":"Microorganisms"},{"key":"pone.0303285.ref009","first-page":"97","article-title":"Antibacterianos: principais classes, mecanismos de a\u00e7\u00e3o e resist\u00eancia","volume":"18","author":"HS Nogueira","year":"2016","journal-title":"Rev Unim Cient"},{"issue":"10","key":"pone.0303285.ref010","doi-asserted-by":"crossref","first-page":"1883","DOI":"10.1016\/j.drudis.2020.07.011","article-title":"Computational approaches in efflux pump inhibitors: current status and prospects","volume":"25","author":"E Rathi","year":"2020","journal-title":"Drug Discovery Today"},{"key":"pone.0303285.ref011","doi-asserted-by":"crossref","first-page":"114589","DOI":"10.1016\/j.jep.2021.114589","article-title":"Role of medicinal plants from North Western Himalayas as an efflux pump inhibitor against MDR AcrAB-TolC Salmonella enterica serovar typhimurium: In vitro and In silico studies","volume":"282","author":"J Mehta","year":"2022","journal-title":"Journal of Ethnopharmacology"},{"issue":"8","key":"pone.0303285.ref012","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/j.resmic.2019.06.001","article-title":"Multidrug ABC transporters in bacteria","volume":"170","author":"C Orelle","year":"2019","journal-title":"Research in Microbiology"},{"issue":"2","key":"pone.0303285.ref013","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1128\/CMR.00117-14","article-title":"The challenge of efflux-mediated antibiotic resistance in Gram-negative bacteria","volume":"28","author":"XZ Li","year":"2015","journal-title":"Clinical Microbiology Reviews"},{"issue":"1","key":"pone.0303285.ref014","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1574-695X.2011.00831.x","article-title":"Efflux as a mechanism for drug resistance in Mycobacterium tuberculosis","volume":"63","author":"PE da Silva","year":"2011","journal-title":"FEMS Immunology & Medical Microbiology"},{"issue":"6","key":"pone.0303285.ref015","doi-asserted-by":"crossref","first-page":"1354","DOI":"10.1111\/j.1365-2958.2010.07319.x","article-title":"The maltose ATP\u2010binding cassette transporter in the 21st century\u2013towards a structural dynamic perspective on its mode of action","volume":"77","author":"E Bordignon","year":"2010","journal-title":"Molecular Microbiology"},{"issue":"5","key":"pone.0303285.ref016","doi-asserted-by":"crossref","first-page":"2491","DOI":"10.1128\/AAC.02293-13","article-title":"Energy metabolism and drug efflux in Mycobacterium tuberculosis","volume":"58","author":"PA Black","year":"2014","journal-title":"Antimicrobial Agents and Chemotherapy"},{"key":"pone.0303285.ref017","doi-asserted-by":"crossref","first-page":"576559","DOI":"10.3389\/fonc.2020.576559","article-title":"P-glycoprotein: one mechanism, many tasks and the consequences for pharmacotherapy of cancers","volume":"10","author":"A Seelig","year":"2020","journal-title":"Frontiers in Oncology"},{"key":"pone.0303285.ref018","doi-asserted-by":"crossref","first-page":"1303","DOI":"10.1007\/s42770-021-00492-5","article-title":"Potential of 1-(1-napthylmethyl)-piperazine, an efflux pump inhibitor against cadmium-induced multidrug resistance in Salmonella enterica serovar Typhi as an adjunct to antibiotics","volume":"52","author":"UJ Kaur","year":"2021","journal-title":"Brazilian Journal of Microbiology"},{"issue":"7","key":"pone.0303285.ref019","doi-asserted-by":"crossref","first-page":"2989","DOI":"10.1021\/cr9000226","article-title":"ABC efflux pump-based resistance to chemotherapy drugs","volume":"109","author":"PD Eckford","year":"2009","journal-title":"Chemical Reviews"},{"issue":"48","key":"pone.0303285.ref020","doi-asserted-by":"crossref","first-page":"84559","DOI":"10.18632\/oncotarget.19187","article-title":"Novel strategies to prevent the development of multidrug resistance (MDR) in cancer","volume":"8","author":"J Wang","year":"2017","journal-title":"Oncotarget"},{"issue":"3","key":"pone.0303285.ref021","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1111\/j.1742-4658.2009.07486.x","article-title":"Multidrug efflux pumps: The structures of prokaryotic ATP\u2010binding cassette transporter efflux pumps and implications for our understanding of eukaryotic P\u2010glycoproteins and homologues","volume":"277","author":"ID Kerr","year":"2010","journal-title":"The FEBS Journal"},{"issue":"3","key":"pone.0303285.ref022","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1128\/MMBR.00001-07","article-title":"Distribution and physiology of ABC-type transporters contributing to multidrug resistance in bacteria","volume":"71","author":"J Lubelski","year":"2007","journal-title":"Microbiology and Molecular Biology Reviews"},{"issue":"22","key":"pone.0303285.ref023","doi-asserted-by":"crossref","first-page":"57","DOI":"10.4103\/phrev.phrev_21_17","article-title":"Developing new antimicrobial therapies: are synergistic combinations of plant extracts\/compounds with conventional antibiotics the solution?","volume":"11","author":"MJ Cheesman","year":"2017","journal-title":"Pharmacognosy Reviews"},{"issue":"6","key":"pone.0303285.ref024","doi-asserted-by":"crossref","first-page":"2375","DOI":"10.1002\/ptr.7456","article-title":"A review: Pharmacology and pharmacokinetics of Schisandrin A","volume":"36","author":"K Fu","year":"2022","journal-title":"Phytotherapy Research"},{"issue":"2","key":"pone.0303285.ref025","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1016\/j.bbrc.2005.07.097","article-title":"Schisandrin B\u2014a novel inhibitor of P-glycoprotein","volume":"335","author":"P Qiangrong","year":"2005","journal-title":"Biochemical and Biophysical Research Communications"},{"key":"pone.0303285.ref026","doi-asserted-by":"crossref","first-page":"154209","DOI":"10.1016\/j.phymed.2022.154209","article-title":"Schisandrin C improves leaky gut conditions in intestinal cell monolayer, organoid, and nematode models by increasing tight junction protein expression","volume":"103","author":"MR Kim","year":"2022","journal-title":"Phytomedicine"},{"issue":"45","key":"pone.0303285.ref027","doi-asserted-by":"crossref","first-page":"29197","DOI":"10.1039\/D2RA02389J","article-title":"Antimicrobial activities and mechanisms of extract and components of herbs in East Asia","volume":"12","author":"J Liang","year":"2022","journal-title":"RSC Advances"},{"key":"pone.0303285.ref028","first-page":"293","article-title":"A novel antimicrobial endolysin, LysPA26, against Pseudomonas aeruginosa","volume":"27","author":"M Guo","year":"2017","journal-title":"Frontiers in Microbiology"},{"issue":"3","key":"pone.0303285.ref029","doi-asserted-by":"crossref","first-page":"458","DOI":"10.3390\/biom11030458","article-title":"A molecular modeling approach to identify potential antileishmanial compounds against the cell division cycle (Cdc)-2-related kinase 12 (crk12) receptor of Leishmania donovani","volume":"11","author":"E Broni","year":"2021","journal-title":"Biomolecules"},{"issue":"7873","key":"pone.0303285.ref030","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1038\/s41586-021-03819-2","article-title":"Highly accurate protein structure prediction with AlphaFold","volume":"596","author":"J Jumper","year":"2021","journal-title":"Nature"},{"issue":"9","key":"pone.0303285.ref031","doi-asserted-by":"crossref","first-page":"1511","DOI":"10.1002\/pro.5560020916","article-title":"Verification of protein structures: patterns of nonbonded atomic interactions","volume":"2","author":"C Colovos","year":"1993","journal-title":"Protein Science"},{"issue":"1","key":"pone.0303285.ref032","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1006\/jmbi.1996.0628","article-title":"Deviations from standard atomic volumes as a quality measure for protein crystal structures","volume":"264","author":"J Pontius","year":"1996","journal-title":"Journal of Molecular Biology"},{"key":"pone.0303285.ref033","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1742-4682-6-9","article-title":"Theoretical study of the Usutu virus helicase 3D structure, by means of computer-aided homology modelling","volume":"6","author":"D Vlachakis","year":"2009","journal-title":"Theoretical Biology and Medical Modelling"},{"issue":"3","key":"pone.0303285.ref034","first-page":"437","volume":"50","author":"SC Lovell","year":"2003","journal-title":"Structure validation: Structure, Function, and Bioinformatics"},{"issue":"11","key":"pone.0303285.ref035","doi-asserted-by":"crossref","first-page":"4058","DOI":"10.3390\/ijms21114058","article-title":"Homology modeling of the human P-glycoprotein (ABCB1) and insights into ligand binding through molecular docking studies","volume":"21","author":"L Mora Lagares","year":"2020","journal-title":"International Journal of Molecular Sciences"},{"issue":"W1","key":"pone.0303285.ref036","doi-asserted-by":"crossref","first-page":"W159","DOI":"10.1093\/nar\/gkac394","article-title":"CB-Dock2: Improved protein\u2013ligand blind docking by integrating cavity detection, docking and homologous template fitting","volume":"50","author":"Y Liu","year":"2022","journal-title":"Nucleic Acids Research"},{"key":"pone.0303285.ref037","doi-asserted-by":"crossref","first-page":"100063","DOI":"10.1016\/j.hazl.2022.100063","article-title":"Structural, functional, and molecular docking analyses of microbial cutinase enzymes against polyurethane monomers","volume":"3","author":"N Flores-Casta\u00f1\u00f3n","year":"2022","journal-title":"Journal of Hazardous Materials Letters"},{"issue":"4","key":"pone.0303285.ref038","doi-asserted-by":"crossref","first-page":"357","DOI":"10.3390\/biomedicines9040357","article-title":"Screening of natural compounds as P-glycoprotein inhibitors against multidrug resistance","volume":"9","author":"SM Marques","year":"2021","journal-title":"Biomedicines"},{"issue":"10","key":"pone.0303285.ref039","doi-asserted-by":"crossref","first-page":"1735","DOI":"10.1016\/j.str.2013.08.005","article-title":"High-resolution comparative modeling with RosettaCM","volume":"21","author":"Y Song","year":"2013","journal-title":"Structure"},{"issue":"8","key":"pone.0303285.ref040","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1038\/nbt0804-1035","article-title":"Where did the BLOSUM62 alignment score matrix come from?","volume":"22","author":"SR Eddy","year":"2004","journal-title":"Nature Biotechnology"},{"issue":"1","key":"pone.0303285.ref041","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12866-018-1332-3","article-title":"Multi-drug resistant Salmonella enterica serovar Typhi isolates with reduced susceptibility to ciprofloxacin in Kenya","volume":"18","author":"WC Mutai","year":"2018","journal-title":"BMC Microbiology"},{"issue":"1","key":"pone.0303285.ref042","first-page":"1","article-title":"The phylogeography and incidence of multi-drug resistant typhoid fever in sub-Saharan Africa","volume":"9","author":"SE Park","year":"2018","journal-title":"Nature Communications"},{"issue":"10","key":"pone.0303285.ref043","doi-asserted-by":"crossref","first-page":"2006","DOI":"10.3390\/microorganisms10102006","article-title":"Understanding the mechanism of antimicrobial resistance and pathogenesis of Salmonella enterica Serovar Typhi","volume":"10","author":"M Khan","year":"2022","journal-title":"Microorganisms"},{"issue":"9","key":"pone.0303285.ref044","doi-asserted-by":"crossref","first-page":"1757","DOI":"10.1016\/j.bbamem.2008.06.009","article-title":"ATP-binding cassette transporters in Escherichia coli","volume":"1778","author":"A Moussatova","year":"2008","journal-title":"Biochimica et Biophysica Acta (BBA)-Biomembranes"},{"key":"pone.0303285.ref045","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1016\/j.biopha.2017.10.145","article-title":"An overview of neuroprotective and cognitive enhancement properties of lignans from Schisandra chinensis","volume":"97","author":"K Sowndhararajan","year":"2018","journal-title":"Biomedicine & Pharmacotherapy"},{"issue":"10","key":"pone.0303285.ref046","doi-asserted-by":"crossref","first-page":"1666","DOI":"10.1038\/s41591-021-01533-0","article-title":"AlphaFold heralds a data-driven revolution in biology and medicine","volume":"27","author":"JM Thornton","year":"2021","journal-title":"Nature Medicine"},{"issue":"8","key":"pone.0303285.ref047","doi-asserted-by":"crossref","first-page":"e4379","DOI":"10.1002\/pro.4379","article-title":"Benchmarking AlphaFold for protein complex modeling reveals accuracy determinants","volume":"31","author":"R Yin","year":"2022","journal-title":"Protein Science"},{"key":"pone.0303285.ref048","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1126\/science.1853201","article-title":"A method to identify protein sequences that fold into a known three-dimensional structure","volume":"253","author":"JU Bowie","year":"1991","journal-title":"Science"},{"key":"pone.0303285.ref049","volume-title":"Biomarkers and Bioanalysis Overview","author":"A Kumar","year":"2020"}],"updated-by":[{"DOI":"10.1371\/journal.pone.0320534","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2025,3,19]],"date-time":"2025-03-19T00:00:00Z","timestamp":1742342400000}}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0303285","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,25]],"date-time":"2024-06-25T19:00:20Z","timestamp":1719342020000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0303285"}},"subtitle":[],"editor":[{"given":"Ahmed A.","family":"Al-Karmalawy","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2024,6,25]]},"references-count":49,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2024,6,25]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0303285","relation":{"correction":[{"id-type":"doi","id":"10.1371\/journal.pone.0320534","asserted-by":"object"}]},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,6,25]]}}}