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We had previously reported that\n            <jats:italic>E. coli<\/jats:italic>\n            rapidly accumulated mutations in the\n            <jats:italic>mgrB<\/jats:italic>\n            gene, a negative feedback regulator of PhoQP, when evolved in the antibiotic trimethoprim. Here, we first show that trimethoprim-selected mutations in\n            <jats:italic>mgrB<\/jats:italic>\n            either lower its expression or alter the C-terminus of the MgrB protein and prevent interaction with PhoQ. Both mechanisms compromise MgrB activity, leading to PhoQP hyperactivation and overexpression of dihydrofolate reductase (\n            <jats:italic>folA<\/jats:italic>\n            ), which is the target of trimethoprim. We then investigate the consequences of deregulating PhoQP for the fitness of\n            <jats:italic>E. coli<\/jats:italic>\n            and elucidate the underlying mechanisms. Using laboratory evolution, we demonstrate that\n            <jats:italic>mgrB<\/jats:italic>\n            mutations facilitate rapid fixation of resistant bacteria in populations evolving in trimethoprim, even though their independent effect on drug IC50 is nominal. This effect is explained by a pervasive transcriptional response to deregulated PhoQP, specifically on the downstream RstA-regulon, in addition to activating\n            <jats:italic>folA<\/jats:italic>\n            transcription. Pervasive gene deregulation also explained the fitness costs of\n            <jats:italic>mgrB<\/jats:italic>\n            mutations, although involving different molecular players. PhoQP hyperactivation perturbed the balance of RpoS- and RpoD-regulated transcriptional programs and mutations that reset this balance-restored bacterial fitness in antibiotic-free conditions. Our study shows that the deregulation of a single signaling pathway permeates the wider gene expression network and leads to adaptation or maladaptation depending on the environmental context. The implications of our findings for the evolution of feedback mechanisms in two-component signaling are discussed.\n          <\/jats:p>\n          <jats:sec>\n            <jats:title>IMPORTANCE<\/jats:title>\n            <jats:p>\n              Bacteria employ a number of mechanisms to adapt to antibiotics. Mutations in transcriptional regulators alter the expression levels of genes that can change the susceptibility of bacteria to antibiotics. Two-component signaling proteins are a major class of signaling molecule used by bacteria to regulate transcription. In previous work, we found that mutations in MgrB, a feedback regulator of the PhoQP two-component system, conferred trimethoprim tolerance to\n              <jats:italic>Escherichia coli<\/jats:italic>\n              . Here, we elucidate how mutations in MgrB have a domino-like effect on the gene regulatory network of\n              <jats:italic>E. coli<\/jats:italic>\n              . As a result, pervasive perturbation of gene regulation ensues. Depending on the environmental context, this pervasive deregulation is either adaptive or maladaptive. Our study sheds light on how deregulation of gene expression can be beneficial for bacteria when challenged with antibiotics, and why regulators like MgrB may have evolved in the first place.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1128\/mbio.02119-23","type":"journal-article","created":{"date-parts":[[2023,11,30]],"date-time":"2023-11-30T14:02:06Z","timestamp":1701352926000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":12,"title":["Pervasive gene deregulation underlies adaptation and maladaptation in trimethoprim-resistant\n            <i>E. coli<\/i>"],"prefix":"10.1128","volume":"14","author":[{"given":"Rhea","family":"Vinchhi","sequence":"first","affiliation":[{"name":"Department of Biology, Indian Institute of Science Education and Research, Pashan, Pune, 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