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Resistant strains complicate treatment, which often requires prolonged use of toxic second- and third-line drugs. Protein phosphorylation plays critical roles in\n                      <jats:italic toggle=\"yes\">Mycobacterium tuberculosis<\/jats:italic>\n                      , with serine\/threonine kinases PknA, PknB, and PknG being essential for survival, virulence, and persistence. In this study, we screened an in-house kinase inhibitor library to identify compounds targeting these kinases. Four structurally diverse hits from the screening inhibiting all three kinases\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      were selected for further analysis. Hits were evaluated for their ability to inhibit\n                      <jats:italic toggle=\"yes\">M. tuberculosis<\/jats:italic>\n                      growth and characterized structurally using X-ray crystallography, molecular docking, and isothermal titration calorimetry. Our findings provide a structural framework for the development of multitargeting kinase inhibitors, offering a potential strategy to combat drug-resistant\n                      <jats:italic toggle=\"yes\">M. tuberculosis<\/jats:italic>\n                      .\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        Drug-resistant tuberculosis is a growing global health threat that is increasingly difficult to treat with existing antibiotics, necessitating the discovery of new therapeutic strategies. This study focuses on protein kinases, key regulatory enzymes that help\n                        <jats:italic toggle=\"yes\">Mycobacterium tuberculosis<\/jats:italic>\n                        survive, cause disease, and persist in the host. By identifying small molecules that can simultaneously block multiple essential kinases, this work introduces a promising multitarget approach to combat tuberculosis. Using structural and biophysical methods, we reveal how these compounds interact with their targets, providing a clear blueprint for improving their effectiveness. These insights advance the rational design of next-generation antitubercular drugs and open new avenues for tackling multidrug- and extensively drug-resistant tuberculosis.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/spectrum.00049-26","type":"journal-article","created":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T13:00:15Z","timestamp":1784034015000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Structural insights into multitargeting\n                    <i>Mycobacterium tuberculosis<\/i>\n                    Pkn kinases"],"prefix":"10.1128","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-5949-6122","authenticated-orcid":false,"given":"Angelika","family":"P\u00f6ll\u00e4niemi","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/033003e23","id-type":"ROR","asserted-by":"publisher"}],"name":"Faculty of Medicine and Health Technology, Tampere University","place":["Tampere, Finland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ya","family":"Miao","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/033003e23","id-type":"ROR","asserted-by":"publisher"}],"name":"Faculty of Medicine and Health Technology, Tampere University","place":["Tampere, Finland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lotta","family":"Laitila","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/033003e23","id-type":"ROR","asserted-by":"publisher"}],"name":"Faculty of Medicine and Health Technology, Tampere University","place":["Tampere, Finland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannaleena","family":"Piippo","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/033003e23","id-type":"ROR","asserted-by":"publisher"}],"name":"Faculty of Medicine and Health Technology, Tampere University","place":["Tampere, Finland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9076-8782","authenticated-orcid":true,"given":"Milka","family":"Hammar\u00e9n","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/033003e23","id-type":"ROR","asserted-by":"publisher"}],"name":"Faculty of Medicine and Health Technology, Tampere University","place":["Tampere, Finland"]},{"id":[{"id":"https:\/\/ror.org\/01zjc6908","id-type":"ROR","asserted-by":"publisher"}],"name":"European Molecular Biology Laboratory","place":["Heidelberg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mataleena","family":"Parikka","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/033003e23","id-type":"ROR","asserted-by":"publisher"}],"name":"Faculty of Medicine and Health Technology, Tampere University","place":["Tampere, Finland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8441-2517","authenticated-orcid":true,"given":"Teemu","family":"Haikarainen","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/033003e23","id-type":"ROR","asserted-by":"publisher"}],"name":"Faculty of Medicine and Health Technology, Tampere University","place":["Tampere, Finland"]},{"name":"Fimlab Laboratories","place":["Tampere, Finland"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.rmed.2006.08.006"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.15167\/2421-4248\/jpmh2017.58.1.728"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/502S2a"},{"key":"e_1_3_4_5_2","volume-title":"Global tuberculosis report 2025","author":"World Health Organization","year":"2025","unstructured":"World Health Organization. 2025. 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