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Classically, individual TCSs have been viewed as simple input\u2013output systems, in which signal propagate via phosphorylation from the HK to the cognate RR, the latter triggering downstream functions. Emerging evidence suggests that TCSs can also operate through intricate networks, collectively sensing multiple inputs and generating fine-tuned, concerted, diversified, and complex outputs, modulated by several factors such as TCS-dependent cross-talk, additional layers of posttranslational modifications, external protein-based signalling input or adaptor molecules, and small RNAs. In this review, using evidence from mycobacterial TCSs, we discuss how TCSs can function as multiple input\u2013multiple output (MIMO) hubs, thereby serving as signal integration and dispersion units to generate complex adaptive responses tuned by many modulating factors. We also discuss how the MIMO landscape of TCSs drives bacterial adaptation and presents potential strategies for therapeutic intervention.<\/jats:p>","DOI":"10.1093\/femsre\/fuaf064","type":"journal-article","created":{"date-parts":[[2025,12,13]],"date-time":"2025-12-13T12:45:05Z","timestamp":1765629905000},"source":"Crossref","is-referenced-by-count":1,"title":["Multiple input\u2013multiple output (MIMO) designs in two-component signalling systems of\n                    <i>Mycobacterium tuberculosis<\/i>"],"prefix":"10.1093","volume":"50","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0247-4766","authenticated-orcid":false,"given":"Devendra Pratap","family":"Singh","sequence":"first","affiliation":[{"name":"Indian Institute of Science Department of Developmental Biology and Genetics, , Bangalore 560012 ,","place":["India"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gayathri","family":"A S","sequence":"additional","affiliation":[{"name":"Indian Institute of Science Department of Developmental Biology and Genetics, , Bangalore 560012 ,","place":["India"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ramandeep","family":"Singh","sequence":"additional","affiliation":[{"name":"Tuberculosis Research Laboratory, Translational Health Science and Technology Institute, National Capital Region Biotech Science Cluster Centre for Tuberculosis Research, , Faridabad 121001 ,","place":["India"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Narendra M","family":"Dixit","sequence":"additional","affiliation":[{"name":"Indian Institute of Science Department of Chemical Engineering, , Bangalore 560012 ,","place":["India"]},{"name":"Indian Institute of Science Department of Bioengineering, , Bangalore 560012 ,","place":["India"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6671-7256","authenticated-orcid":false,"given":"Deepak 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