{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T01:15:01Z","timestamp":1788225301954,"version":"build-2803163510"},"reference-count":60,"publisher":"American Society for Microbiology","issue":"2","license":[{"start":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T00:00:00Z","timestamp":1770076800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T00:00:00Z","timestamp":1770076800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/501100001407","name":"Department of Biotechnology, Ministry of Science and Technology, India","doi-asserted-by":"publisher","award":["BT\/PR31937\/MED\/29\/1404\/2019"],"award-info":[{"award-number":["BT\/PR31937\/MED\/29\/1404\/2019"]}],"id":[{"id":"10.13039\/501100001407","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001407","name":"Department of Biotechnology, Ministry of Science and Technology, India","doi-asserted-by":"publisher","award":["BT\/PR41993\/MED\/29\/1559\/2021"],"award-info":[{"award-number":["BT\/PR41993\/MED\/29\/1559\/2021"]}],"id":[{"id":"10.13039\/501100001407","id-type":"DOI","asserted-by":"publisher"}]},{"name":"BIRAC, DBT","award":["BIRAC\/PMU\/2019\/Sentinels-001"],"award-info":[{"award-number":["BIRAC\/PMU\/2019\/Sentinels-001"]}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Microbiol Spectr"],"published-print":{"date-parts":[[2026,2,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      Two-component signaling systems (TCSSs) serve as primary signal transduction pathways in bacteria, regulating essential processes including growth, physiology, and virulence, making them attractive drug targets. In\n                      <jats:italic toggle=\"yes\">Mycobacterium tuberculosis<\/jats:italic>\n                      (\n                      <jats:italic toggle=\"yes\">M. tb<\/jats:italic>\n                      ), the PhoPR system plays a critical role in pathogenesis, with the PhoR histidine kinase (HK) functioning at the intersection of cognate and noncognate signaling networks. Using PhoR as a prototypical HK, we hypothesized that targeting this system would compromise\n                      <jats:italic toggle=\"yes\">M. tb\u2019s<\/jats:italic>\n                      adaptive capacity. We developed and optimized a high-throughput screen of pharmacologically active small-molecule libraries to identify PhoR autophosphorylation inhibitors. Selected compounds were evaluated using kinase assays, protein interaction analyses, molecular docking studies, and growth inhibition using\n                      <jats:italic toggle=\"yes\">Mycobacterium bovis<\/jats:italic>\n                      BCG. Screening identified 11 potential inhibitors, with tamoxifen (TAM) demonstrating the most potent activity. TAM inhibited PhoR autophosphorylation at micromolar concentrations both\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      . Mechanistic studies revealed that TAM competitively binds to the ATP-binding pocket of PhoR with a dissociation constant (K\n                      <jats:sub>d<\/jats:sub>\n                      ) of 108.5 \u00b1 44 nM. Although maximum inhibition was found with PhoR, additional screening of HKs revealed MtrB as another low-affinity target of TAM (K\n                      <jats:sub>d<\/jats:sub>\n                      = 412 \u00b1 83 nM). Treatment with TAM significantly inhibited\n                      <jats:italic toggle=\"yes\">M. bovis<\/jats:italic>\n                      BCG growth in culture and suppressed PhoPR-regulated acid-responsive gene expression. Our findings establish PhoR HK as a promising antimycobacterial drug target and demonstrate the potential for repurposing the clinically approved anticancer drug TAM as an anti-tuberculosis therapeutic with TCS-targeting effects. This work provides proof of concept for targeting bacterial TCSSs and supports further development of TAM derivatives for tuberculosis treatment.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        Two-component signaling systems are essential for bacterial growth, metabolism, and survival, making them ideal candidates for selective antimicrobial therapy. Tamoxifen (TAM), a well-known anticancer drug, has recently been shown to exhibit antimicrobial activity and is emerging as a potential anti-tuberculosis (TB) agent. In this study, we report for the first time that TAM inhibits\n                        <jats:italic toggle=\"yes\">Mycobacterium tuberculosis<\/jats:italic>\n                        histidine kinases, PhoR and MtrB, implicated in virulence. Using a combination of biochemical and computational biology techniques, we demonstrate that TAM competes with ATP for PhoR binding and impairs its autophosphorylation activity, thereby disrupting downstream regulation of gene expression. Dissociation kinetics revealed that in comparison to PhoR, TAM bound MtrB with a lower affinity. These findings establish PhoR as a novel drug target, highlight a plausible mechanism of TAM\u2019s antimycobacterial action, and, more importantly, support its repurposing as a promising therapeutic candidate against TB.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/spectrum.01880-25","type":"journal-article","created":{"date-parts":[[2025,12,16]],"date-time":"2025-12-16T14:10:40Z","timestamp":1765894240000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":1,"title":["Tamoxifen inhibits histidine kinases of\n                    <i>M. tuberculosis<\/i>\n                    two-component signaling systems"],"prefix":"10.1128","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3436-2531","authenticated-orcid":true,"given":"Abhishek","family":"Garg","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04gzb2213","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biochemistry, University of Delhi South Campus","place":["New Delhi, India"]},{"name":"Department of Biochemistry, Sri Venkateswara College, University of Delhi","place":["New Delhi, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Devendra Pratap","family":"Singh","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05j873a45","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Developmental Biology and Genetics, Indian Institute of Science","place":["Bengaluru, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mansi","family":"Pandit","sequence":"additional","affiliation":[{"name":"Bioinformatics Infrastructure Facility, Sri Venkateswara College, University of Delhi","place":["New Delhi, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6138-1909","authenticated-orcid":true,"given":"Vandana","family":"Malhotra","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Sri Venkateswara College, University of Delhi","place":["New Delhi, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6671-7256","authenticated-orcid":true,"given":"Deepak Kumar","family":"Saini","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05j873a45","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Developmental Biology and Genetics, Indian Institute of Science","place":["Bengaluru, India"]},{"id":[{"id":"https:\/\/ror.org\/05j873a45","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Bioengineering, Indian Institute of Science","place":["Bengaluru, India"]},{"id":[{"id":"https:\/\/ror.org\/05j873a45","id-type":"ROR","asserted-by":"publisher"}],"name":"Centre for Infectious Disease Research, Indian Institute of Science","place":["Bengaluru, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_5_2_2","volume-title":"StatPearls","author":"Adigun R","year":"2022","unstructured":"Adigun R, Singh R. 2022. 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