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Its chaperone function plays an important role in the growth and survival of <jats:italic>M.\u2009leprae<\/jats:italic> inside infected hosts. HSP18\/18\u2010kDa antigen is often used as a diagnostic marker for determining the efficacy of multidrug therapy (MDT) in leprosy. However, whether MDT drugs (dapsone, clofazimine, and rifampicin) do interact with HSP18 and how these interactions affect its structure and chaperone function is still unclear. Here, we report evidence of HSP18\u2010dapsone\/clofazimine\/rifampicin interaction and its impact on the structure and chaperone function of HSP18. These three drugs interact efficiently with HSP18 (having submicromolar binding affinity) with 1\u2009:\u20091 stoichiometry. Binding of these MDT drugs to the \u2018\u03b1\u2010crystallin domain\u2019 of HSP18 alters its secondary structure and tryptophan micro\u2010environment. Furthermore, surface hydrophobicity, oligomeric size, and thermostability of the protein are reduced upon interaction with these three drugs. Eventually, all these structural alterations synergistically decrease the chaperone function of HSP18. Interestingly, the effect of rifampicin on the structure, stability, and chaperone function of this mycobacterial small heat shock protein is more pronounced than the other two MDT drugs. This reduction in the chaperone function of HSP18 may additionally abate <jats:italic>M.\u2009leprae<\/jats:italic> survivability during multidrug treatment. Altogether, this study provides a possible foundation for rational designing and development of suitable HSP18 inhibitors in the context of effective treatment of leprosy.<\/jats:p>","DOI":"10.1111\/febs.16212","type":"journal-article","created":{"date-parts":[[2021,9,23]],"date-time":"2021-09-23T19:07:21Z","timestamp":1632424041000},"page":"832-853","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Interaction of constituents of MDT regimen for leprosy with <i>Mycobacterium leprae<\/i> HSP18: impact on its structure and function"],"prefix":"10.1111","volume":"289","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1155-7862","authenticated-orcid":false,"given":"Ayon","family":"Chakraborty","sequence":"first","affiliation":[{"name":"School of Basic Sciences Indian Institute of Technology Bhubaneswar India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rajesh","family":"Ghosh","sequence":"additional","affiliation":[{"name":"School of Basic Sciences Indian Institute of Technology Bhubaneswar India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5209-1130","authenticated-orcid":false,"given":"Ashis","family":"Biswas","sequence":"additional","affiliation":[{"name":"School of Basic Sciences Indian Institute of Technology Bhubaneswar India"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2021,10,10]]},"reference":[{"key":"e_1_2_9_2_1","first-page":"298","article-title":"The promin treatment of leprosy. 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