{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T03:46:34Z","timestamp":1791776794559,"version":"4.3.4"},"reference-count":100,"publisher":"eLife Sciences Publications, Ltd","license":[{"start":{"date-parts":[[2021,9,30]],"date-time":"2021-09-30T00:00:00Z","timestamp":1632960000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2021,9,30]],"date-time":"2021-09-30T00:00:00Z","timestamp":1632960000000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2021,9,30]],"date-time":"2021-09-30T00:00:00Z","timestamp":1632960000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001409","name":"Department of Science and Technology, Ministry of Science and Technology, India","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001409","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001843","name":"Science and Engineering Research Board","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001843","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["elifesciences.org"],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2021,9,22]]},"abstract":"<jats:p>\n                    Gene regulatory networks allow organisms to generate coordinated responses to environmental challenges. In bacteria, regulatory networks are re-wired and re-purposed during evolution, though the relationship between selection pressures and evolutionary change is poorly understood. In this study, we discover that the early evolutionary response of\n                    <jats:italic>Escherichia coli<\/jats:italic>\n                    to the antibiotic trimethoprim involves derepression of PhoPQ signaling, an Mg\n                    <jats:sup>2+<\/jats:sup>\n                    -sensitive two-component system, by inactivation of the MgrB feedback-regulatory protein. We report that derepression of PhoPQ confers trimethoprim-tolerance to\n                    <jats:italic>E. coli<\/jats:italic>\n                    by hitherto unrecognized transcriptional upregulation of dihydrofolate reductase (DHFR), target of trimethoprim. As a result, mutations in\n                    <jats:italic>mgrB<\/jats:italic>\n                    precede and facilitate the evolution of drug resistance. Using laboratory evolution, genome sequencing, and mutation re-construction, we show that populations of\n                    <jats:italic>E. coli<\/jats:italic>\n                    challenged with trimethoprim are faced with the evolutionary \u2018choice\u2019 of transitioning from tolerant to resistant by mutations in DHFR, or compensating for the fitness costs of PhoPQ derepression by inactivating the RpoS sigma factor, itself a PhoPQ-target. Outcomes at this evolutionary branch-point are determined by the strength of antibiotic selection, such that high pressures favor resistance, while low pressures favor cost compensation. Our results relate evolutionary changes in bacterial gene regulatory networks to strength of selection and provide mechanistic evidence to substantiate this link.\n                  <\/jats:p>","DOI":"10.7554\/elife.70931","type":"journal-article","created":{"date-parts":[[2021,9,30]],"date-time":"2021-09-30T08:03:43Z","timestamp":1632989023000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.70931","source":"Crossref","is-referenced-by-count":46,"title":["Adaptation and compensation in a bacterial gene regulatory network evolving under antibiotic selection"],"prefix":"10.7554","volume":"10","author":[{"given":"Vishwa","family":"Patel","sequence":"first","affiliation":[{"name":"Dr. Vikram Sarabhai Institute of Cell and Molecular Biology, The Maharaja Sayajirao University of Baroda","place":["Vadodara, India"]},{"name":"Department of Microbiology and Cell Biology, Indian Institute of Science","place":["Bangalore, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2947-3931","authenticated-orcid":true,"given":"Nishad","family":"Matange","sequence":"additional","affiliation":[{"name":"Indian Institute of Science Education and Research (IISER)","place":["Pune, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4374","published-online":{"date-parts":[[2021,9,30]]},"reference":[{"key":"bib1","doi-asserted-by":"publisher","first-page":"465","DOI":"10.1038\/nrmicro3270","article-title":"Microbiological effects of sublethal levels of antibiotics","volume":"12","author":"Andersson","year":"2014","journal-title":"Nature Reviews. Microbiology"},{"key":"bib2","doi-asserted-by":"publisher","DOI":"10.1038\/msb4100050","article-title":"Construction of Escherichia coli k-12 in-frame, single-gene knockout mutants: The Keio Collection","volume":"2","author":"Baba","year":"2006","journal-title":"Molecular Systems Biology"},{"key":"bib3","doi-asserted-by":"publisher","first-page":"461","DOI":"10.1016\/j.cell.2005.05.030","article-title":"Recognition of antimicrobial peptides by a bacterial sensor kinase","volume":"122","author":"Bader","year":"2005","journal-title":"Cell"},{"key":"bib4","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1054\/drup.2001.0196","article-title":"Low-level antibacterial resistance: A gateway to clinical resistance","volume":"4","author":"Baquero","year":"2001","journal-title":"Drug Resistance Updates"},{"key":"bib5","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2010.06.049","article-title":"Using synthetic biology to understand the evolution of gene expression","volume":"20","author":"Bayer","year":"2010","journal-title":"Current Biology"},{"key":"bib6","doi-asserted-by":"publisher","first-page":"1147","DOI":"10.1126\/science.aag0822","article-title":"Spatiotemporal microbial evolution on antibiotic landscapes","volume":"353","author":"Baym","year":"2016","journal-title":"Science"},{"key":"bib7","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1016\/j.mib.2006.01.005","article-title":"Regulation of bacterial virulence by two-component systems","volume":"9","author":"Beier","year":"2006","journal-title":"Current Opinion in Microbiology"},{"key":"bib8","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1021\/cb5007135","article-title":"Bacterial histidine kinases as novel antibacterial drug targets","volume":"10","author":"Bem","year":"2015","journal-title":"ACS Chemical Biology"},{"key":"bib9","doi-asserted-by":"publisher","first-page":"1479","DOI":"10.1126\/science.287.5457.1479","article-title":"Effects of environment on compensatory mutations to ameliorate costs of antibiotic resistance","volume":"287","author":"Bj\u00f6rkman","year":"2000","journal-title":"Science"},{"key":"bib10","doi-asserted-by":"publisher","first-page":"5521","DOI":"10.1128\/AAC.01480-13","article-title":"In vivo emergence of colistin resistance in Klebsiella pneumoniae producing kpc-type carbapenemases mediated by insertional inactivation of the PHOQ\/PHOP Mgrb regulator","volume":"57","author":"Cannatelli","year":"2013","journal-title":"Antimicrobial Agents and Chemotherapy"},{"key":"bib11","doi-asserted-by":"publisher","first-page":"7915","DOI":"10.1128\/AEM.05274-11","article-title":"Phenotypic diversity caused by differential rpos activity among environmental Escherichia coli isolates","volume":"77","author":"Chiang","year":"2011","journal-title":"Applied and Environmental Microbiology"},{"key":"bib12","doi-asserted-by":"publisher","first-page":"400","DOI":"10.1007\/BF00325901","article-title":"Characterisation of the promoter for the LEXA regulated sula gene of Escherichia coli","volume":"189","author":"Cole","year":"1983","journal-title":"Molecular & General Genetics"},{"key":"bib13","doi-asserted-by":"publisher","first-page":"7184","DOI":"10.1128\/JB.185.24.7184-7192.2003","article-title":"The CRORS two-component regulatory system is required for intrinsic beta-lactam resistance in Enterococcus faecalis","volume":"185","author":"Comenge","year":"2003","journal-title":"Journal of Bacteriology"},{"key":"bib14","doi-asserted-by":"publisher","first-page":"6640","DOI":"10.1073\/pnas.120163297","article-title":"One-step inactivation of chromosomal genes in Escherichia coli K-12 using PCR products","volume":"97","author":"Datsenko","year":"2000","journal-title":"PNAS"},{"key":"bib15","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1007\/978-1-4939-0554-6_12","article-title":"Identification of mutations in laboratory-evolved microbes from next-generation sequencing data using BRESEQ","volume":"1151","author":"Deatherage","year":"2014","journal-title":"Methods in Molecular Biology"},{"key":"bib16","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2180-9-118","article-title":"Polymorphism and selection of rpos in pathogenic Escherichia coli","volume":"9","author":"Dong","year":"2009","journal-title":"BMC Microbiology"},{"key":"bib17","doi-asserted-by":"publisher","first-page":"18712","DOI":"10.1073\/pnas.0705768104","article-title":"B1500, a small membrane protein, connects the two-component systems EVGS\/EVGA and PHOQ\/PHOP in Escherichia coli","volume":"104","author":"Eguchi","year":"2007","journal-title":"PNAS"},{"key":"bib18","doi-asserted-by":"publisher","first-page":"1222","DOI":"10.1128\/JB.01124-10","article-title":"Regulation of acid resistance by connectors of two-component signal transduction systems in Escherichia coli","volume":"193","author":"Eguchi","year":"2011","journal-title":"Journal of Bacteriology"},{"key":"bib19","doi-asserted-by":"publisher","first-page":"676","DOI":"10.1038\/nsmb1115","article-title":"Structural basis for atp-dependent DNAA assembly and replication-origin remodeling","volume":"13","author":"Erzberger","year":"2006","journal-title":"Nature Structural & Molecular Biology"},{"key":"bib20","doi-asserted-by":"publisher","first-page":"473","DOI":"10.1111\/j.1432-1033.1987.tb10664.x","article-title":"Massive overproduction of dihydrofolate reductase in bacteria as a response to the use of trimethoprim","volume":"162","author":"Flensburg","year":"1987","journal-title":"European Journal of Biochemistry"},{"key":"bib21","doi-asserted-by":"publisher","first-page":"D133","DOI":"10.1093\/nar\/gkv1156","article-title":"Regulondb version 9.0: High-level integration of gene regulation, coexpression, motif clustering and beyond","volume":"44","author":"Gama-Castro","year":"2016","journal-title":"Nucleic Acids Research"},{"key":"bib22","doi-asserted-by":"publisher","first-page":"456","DOI":"10.1016\/j.tig.2006.06.002","article-title":"Natural selection on gene expression","volume":"22","author":"Gilad","year":"2006","journal-title":"Trends in Genetics"},{"key":"bib23","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1128\/jb.148.1.265-273.1981","article-title":"Role of sulA and sulB in filamentation by lon mutants of Escherichia coli K-12","volume":"148","author":"Gottesman","year":"1981","journal-title":"Journal of Bacteriology"},{"key":"bib24","doi-asserted-by":"publisher","first-page":"1835","DOI":"10.1128\/JB.183.6.1835-1842.2001","article-title":"The pleiotropic two-component regulatory system PHOP-PHOQ","volume":"183","author":"Groisman","year":"2001","journal-title":"Journal of Bacteriology"},{"key":"bib25","doi-asserted-by":"publisher","first-page":"2049","DOI":"10.1099\/mic.0.066787-0","article-title":"Salmonella enterica SEROVAR TYPHIMURIUM BAESR two-component system positively regulates soda in response to ciprofloxacin","volume":"159","author":"Guerrero","year":"2013","journal-title":"Microbiology"},{"key":"bib26","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1002158","article-title":"Selection of resistant bacteria at very low antibiotic concentrations","volume":"7","author":"Gullberg","year":"2011","journal-title":"PLOS Pathogens"},{"key":"bib27","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1016\/j.tim.2008.03.007","article-title":"The Salmonella PMRAB regulon: Lipopolysaccharide modifications, antimicrobial peptide resistance and more","volume":"16","author":"Gunn","year":"2008","journal-title":"Trends in Microbiology"},{"key":"bib28","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms2607","article-title":"\u03b2-Lactam antibiotics promote bacterial mutagenesis via an RpoS-mediated reduction in replication fidelity","volume":"4","author":"Gutierrez","year":"2013","journal-title":"Nature Communications"},{"key":"bib29","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2015.00499","article-title":"Thymineless death, at the origin","volume":"6","author":"Guzm\u00e1n","year":"2015","journal-title":"Frontiers in Microbiology"},{"key":"bib30","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2017.02470","article-title":"Mgrb alterations mediate colistin resistance in klebsiella pneumoniae isolates from Iran","volume":"8","author":"Haeili","year":"2017","journal-title":"Frontiers in Microbiology"},{"key":"bib31","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.0020137","article-title":"The role of compensatory mutations in the emergence of drug resistance","volume":"2","author":"Handel","year":"2006","journal-title":"PLOS Computational Biology"},{"key":"bib32","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1007\/978-0-387-78885-2_4","article-title":"The two-component network and the general stress Sigma Factor rpos (Sigma s) in Escherichia coli","volume":"631","author":"Hengge","year":"2008","journal-title":"Advances in Experimental Medicine and Biology"},{"key":"bib33","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1009063","article-title":"Mutations in Dnaa and a cryptic interaction site increase drug resistance in mycobacterium tuberculosis","volume":"16","author":"Hicks","year":"2020","journal-title":"PLOS Pathogens"},{"key":"bib34","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1038\/s41576-020-00304-w","article-title":"Molecular and evolutionary processes generating variation in gene expression","volume":"22","author":"Hill","year":"2021","journal-title":"Nature Reviews. Genetics"},{"key":"bib35","doi-asserted-by":"publisher","DOI":"10.1098\/rstb.2016.0039","article-title":"Antibiotic resistance in the wild: An eco-evolutionary perspective","volume":"372","author":"Hiltunen","year":"2017","journal-title":"PNAS"},{"key":"bib36","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2017.00656","article-title":"Hydrophobicity of residue 128 of the stress-inducible sigma factor Rpos is critical for its activity","volume":"8","author":"Iwase","year":"2017","journal-title":"Frontiers in Microbiology"},{"key":"bib37","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1016\/j.ijmm.2007.02.002","article-title":"Role of insertion elements and yycfg in the development of decreased susceptibility to vancomycin in Staphylococcus aureus","volume":"297","author":"Jansen","year":"2007","journal-title":"International Journal of Medical Microbiology"},{"key":"bib38","doi-asserted-by":"publisher","first-page":"1310","DOI":"10.1111\/j.1365-2958.2006.05450.x","article-title":"The exceptionally tight affinity of Dnaa for ATP\/ADP requires a unique aspartic acid residue in the aaa+ Sensor 1 motif","volume":"62","author":"Kawakami","year":"2006","journal-title":"Molecular Microbiology"},{"key":"bib39","doi-asserted-by":"publisher","first-page":"1721","DOI":"10.1111\/eva.12846","article-title":"Recent insights into the genotype-phenotype relationship from massively parallel genetic assays","volume":"12","author":"Kemble","year":"2019","journal-title":"Evolutionary Applications"},{"key":"bib40","doi-asserted-by":"publisher","first-page":"430","DOI":"10.15252\/emmm.201607336","article-title":"A klebsiella pneumoniae antibiotic resistance mechanism that subdues host defences and promotes virulence","volume":"9","author":"Kidd","year":"2017","journal-title":"EMBO Molecular Medicine"},{"key":"bib41","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2012.00227","article-title":"Bridging the gap between genotype and phenotype via network approaches","volume":"3","author":"Kim","year":"2012","journal-title":"Frontiers in Genetics"},{"key":"bib42","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1093\/dnares\/dsi012","article-title":"Complete set of ORF clones of Escherichia coli ASKA library (a complete set of E. coli K-12 ORF archive): Unique resources for biological research","volume":"12","author":"Kitagawa","year":"2005","journal-title":"DNA Research"},{"key":"bib43","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1016\/s0966-842x(02)00005-7","article-title":"Genomic variability among enteric pathogens: The case of the muts-rpos intergenic region","volume":"11","author":"Kotewicz","year":"2003","journal-title":"Trends in Microbiology"},{"key":"bib44","doi-asserted-by":"publisher","first-page":"826","DOI":"10.1126\/science.aaj2191","article-title":"Antibiotic tolerance facilitates the evolution of resistance","volume":"355","author":"Levin-Reisman","year":"2017","journal-title":"Science"},{"key":"bib45","doi-asserted-by":"publisher","first-page":"4936","DOI":"10.1073\/pnas.0408031102","article-title":"Gene regulatory networks for development","volume":"102","author":"Levine","year":"2005","journal-title":"PNAS"},{"key":"bib46","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1000788","article-title":"Feedback inhibition in the PHOQ\/PHOP signaling system by a membrane peptide","volume":"5","author":"Lippa","year":"2009","journal-title":"PLOS Genetics"},{"key":"bib47","doi-asserted-by":"publisher","first-page":"1457","DOI":"10.1128\/JB.06055-11","article-title":"Perturbation of the oxidizing environment of the periplasm stimulates the phoq\/phop system in Escherichia coli","volume":"194","author":"Lippa","year":"2012","journal-title":"Journal of Bacteriology"},{"key":"bib48","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1099\/mic.0.000405","article-title":"Natural Escherichia coli isolates rapidly acquire genetic changes upon laboratory domestication","volume":"163","author":"Liu","year":"2017","journal-title":"Microbiology"},{"key":"bib49","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1007\/s00284-002-3814-6","article-title":"Polymorphism in the Yclc-rpos region of Enterobacteria","volume":"46","author":"Martinez-Garcia","year":"2003","journal-title":"Current Microbiology"},{"key":"bib50","doi-asserted-by":"publisher","first-page":"2107","DOI":"10.1042\/BCJ20180249","article-title":"Trade-offs with stability modulate innate and mutationally acquired drug resistance in bacterial dihydrofolate reductase enzymes","volume":"475","author":"Matange","year":"2018","journal-title":"The Biochemical Journal"},{"key":"bib51","doi-asserted-by":"publisher","first-page":"1029","DOI":"10.1534\/genetics.119.301834","article-title":"Adaptation through lifestyle switching sculpts the fitness landscape of evolving populations: Implications for the selection of drug-resistant bacteria at low drug pressures","volume":"211","author":"Matange","year":"2019","journal-title":"Genetics"},{"key":"bib52","doi-asserted-by":"publisher","DOI":"10.1128\/JB.00561-19","article-title":"Highly contingent phenotypes of Lon protease deficiency in Escherichia coli upon antibiotic challenge","volume":"202","author":"Matange","year":"2020","journal-title":"Journal of Bacteriology"},{"key":"bib53","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1111\/eva.12196","article-title":"The fitness costs of antibiotic resistance mutations","volume":"8","author":"Melnyk","year":"2015","journal-title":"Evolutionary Applications"},{"key":"bib54","doi-asserted-by":"publisher","first-page":"3696","DOI":"10.1128\/JB.185.13.3696-3702.2003","article-title":"Identification and molecular characterization of the mg2+ stimulon of Escherichia coli","volume":"185","author":"Minagawa","year":"2003","journal-title":"Journal of Bacteriology"},{"key":"bib55","doi-asserted-by":"publisher","first-page":"2601","DOI":"10.1101\/gad.1700308","article-title":"Signal integration in bacterial two-component regulatory systems","volume":"22","author":"Mitrophanov","year":"2008","journal-title":"Genes & Development"},{"key":"bib56","doi-asserted-by":"publisher","DOI":"10.1128\/mSystems.00783-20","article-title":"Emerging Transcriptional and Genomic Mechanisms Mediating Carbapenem and Polymyxin Resistance in Enterobacteriaceae: a Systematic Review of Current Reports","volume":"5","author":"Mmatli","year":"2020","journal-title":"MSystems"},{"key":"bib57","doi-asserted-by":"publisher","first-page":"462","DOI":"10.1007\/s00239-004-0212-7","article-title":"Comparison of the PhoPQ regulon in Escherichia coli and Salmonella typhimurium","volume":"60","author":"Monsieurs","year":"2005","journal-title":"Journal of Molecular Evolution"},{"key":"bib58","doi-asserted-by":"publisher","first-page":"4161","DOI":"10.1128\/JB.184.15.4161-4167.2002","article-title":"The putative response regulator BaeR stimulates multidrug resistance of Escherichia coli via a novel multidrug exporter system, MdtABC","volume":"184","author":"Nagakubo","year":"2002","journal-title":"Journal of Bacteriology"},{"key":"bib59","doi-asserted-by":"publisher","first-page":"348","DOI":"10.1111\/j.1365-2958.2010.07110.x","article-title":"A lipoprotein modulates activity of the Mtrab two-component system to provide intrinsic multidrug resistance, cytokinetic control and cell wall homeostasis in mycobacterium","volume":"76","author":"Nguyen","year":"2010","journal-title":"Molecular Microbiology"},{"key":"bib60","doi-asserted-by":"publisher","DOI":"10.1128\/JB.00264-19","article-title":"Phop-mediated repression of the spi1 type 3 secretion system in Salmonella enterica SEROVAR typhimurium","volume":"201","author":"Palmer","year":"2019","journal-title":"Journal of Bacteriology"},{"key":"bib61","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1000428","article-title":"Evolution of a bacterial regulon controlling virulence and Mg(2+) homeostasis","volume":"5","author":"Perez","year":"2009","journal-title":"PLOS Genetics"},{"key":"bib62","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1016\/s0966-842x(99)01458-4","article-title":"Signalling pathways in two-component phosphorelay systems","volume":"7","author":"Perraud","year":"1999","journal-title":"Trends in Microbiology"},{"key":"bib63","doi-asserted-by":"publisher","first-page":"8761","DOI":"10.1074\/jbc.M312080200","article-title":"Czcr-czcs, a two-component system involved in heavy metal and carbapenem resistance in Pseudomonas aeruginosa","volume":"279","author":"Perron","year":"2004","journal-title":"The Journal of Biological Chemistry"},{"key":"bib64","doi-asserted-by":"publisher","DOI":"10.1099\/mgen.0.000158","article-title":"Multifactorial chromosomal variants regulate polymyxin resistance in extensively drug-resistant Klebsiella pneumoniae","volume":"4","author":"Pitt","year":"2018","journal-title":"Microbial Genomics"},{"key":"bib65","article-title":"The genomic basis of adaptation to the fitness cost of rifampicin resistance in Pseudomonas aeruginosa proceedings","volume":"283","author":"Qi","year":"2016","journal-title":"Biological Sciences"},{"key":"bib66","doi-asserted-by":"publisher","first-page":"1789","DOI":"10.1016\/S0021-9258(18)91259-7","article-title":"Substrate Specificity and Induction of Thymidine Phosphorylase in Escherichia coli","volume":"239","author":"Razzell","year":"1964","journal-title":"The Journal of Biological Chemistry"},{"key":"bib67","doi-asserted-by":"publisher","first-page":"E1470","DOI":"10.1073\/pnas.1601441113","article-title":"Biophysical principles predict fitness landscapes of drug resistance","volume":"113","author":"Rodrigues","year":"2016","journal-title":"PNAS"},{"key":"bib68","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.50509","article-title":"Adaptation to mutational inactivation of an essential gene converges to an accessible suboptimal fitness peak","volume":"8","author":"Rodrigues","year":"2019","journal-title":"eLife"},{"key":"bib69","doi-asserted-by":"publisher","first-page":"430","DOI":"10.1111\/mmi.13471","article-title":"The small membrane protein MGRB regulates PHOQ bifunctionality to control phop target gene expression dynamics","volume":"102","author":"Salazar","year":"2016","journal-title":"Molecular Microbiology"},{"key":"bib70","doi-asserted-by":"publisher","first-page":"690","DOI":"10.1038\/s41589-019-0286-6","article-title":"Rewiring bacterial two-component systems by modular dna-binding domain swapping","volume":"15","author":"Schmidl","year":"2019","journal-title":"Nature Chemical Biology"},{"key":"bib71","doi-asserted-by":"publisher","first-page":"2085","DOI":"10.1128\/AAC.01460-09","article-title":"Compensation of fitness costs and reversibility of antibiotic resistance mutations","volume":"54","author":"Schulz zur Wiesch","year":"2010","journal-title":"Antimicrobial Agents and Chemotherapy"},{"key":"bib72","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1038\/ng881","article-title":"Network motifs in the transcriptional regulation network of Escherichia coli","volume":"31","author":"Shen-Orr","year":"2002","journal-title":"Nature Genetics"},{"key":"bib73","doi-asserted-by":"publisher","first-page":"613","DOI":"10.1128\/JB.01502-07","article-title":"Bioinformatics and experimental analysis of proteins of two-component systems in Myxococcus xanthus","volume":"190","author":"Shi","year":"2008","journal-title":"Journal of Bacteriology"},{"key":"bib74","doi-asserted-by":"publisher","first-page":"532","DOI":"10.1016\/j.tig.2018.03.007","article-title":"The Evolution of Gene Expression in cis and trans","volume":"34","author":"Signor","year":"2018","journal-title":"Trends in Genetics"},{"key":"bib75","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1016\/j.jgar.2020.11.003","article-title":"Insertion sequences disrupting mgrB in carbapenem-resistant Klebsiella pneumoniae strains in Brazil","volume":"24","author":"Silva","year":"2021","journal-title":"Journal of Global Antimicrobial Resistance"},{"key":"bib76","doi-asserted-by":"publisher","first-page":"1013","DOI":"10.1007\/s00018-017-2679-6","article-title":"Differential gene regulatory networks in development and disease","volume":"75","author":"Singh","year":"2018","journal-title":"Cellular and Molecular Life Sciences"},{"key":"bib77","doi-asserted-by":"publisher","first-page":"259","DOI":"10.3390\/bios3030259","article-title":"The DOSS-DOST\/DOSR mycobacterial sensor system","volume":"3","author":"Sivaramakrishnan","year":"2013","journal-title":"Biosensors"},{"key":"bib78","doi-asserted-by":"publisher","DOI":"10.3390\/biom7040075","article-title":"The Production of Curli Amyloid Fibers Is Deeply Integrated into the Biology of Escherichia coli","volume":"7","author":"Smith","year":"2017","journal-title":"Biomolecules"},{"key":"bib79","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-018-1540-z","article-title":"SKESA: Strategic k-mer extension for scrupulous assemblies","volume":"19","author":"Souvorov","year":"2018","journal-title":"Genome Biology"},{"key":"bib80","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1016\/S0065-2660(07)00006-5","article-title":"Global control regions and regulatory landscapes in vertebrate development and evolution","volume":"61","author":"Spitz","year":"2008","journal-title":"Advances in Genetics"},{"key":"bib81","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1016\/j.femsre.2004.10.003","article-title":"Molecular insights into the initiation of sporulation in gram-positive bacteria: New technologies for an old phenomenon","volume":"29","author":"Stephenson","year":"2005","journal-title":"FEMS Microbiology Reviews"},{"key":"bib82","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1146\/annurev-cellbio-100913-012908","article-title":"Comparative analysis of gene regulatory networks: From network reconstruction to evolution","volume":"31","author":"Thompson","year":"2015","journal-title":"Annual Review of Cell and Developmental Biology"},{"key":"bib83","doi-asserted-by":"publisher","first-page":"533","DOI":"10.2217\/fmb-2019-0002","article-title":"Roles of two-component regulatory systems in antibiotic resistance","volume":"14","author":"Tierney","year":"2019","journal-title":"Future Microbiology"},{"key":"bib84","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1038\/ng.1034","article-title":"Evolutionary paths to antibiotic resistance under dynamically sustained drug selection","volume":"44","author":"Toprak","year":"2011","journal-title":"Nature Genetics"},{"key":"bib85","doi-asserted-by":"publisher","first-page":"701","DOI":"10.1016\/j.resmic.2006.05.004","article-title":"Biological roles of the Lon atp-dependent protease","volume":"157","author":"Tsilibaris","year":"2006","journal-title":"Research in Microbiology"},{"key":"bib86","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2019.02826","article-title":"Diverse fluoroquinolone resistance plasmids from retail meat E. coli in the United States","volume":"10","author":"Tyson","year":"2019","journal-title":"Frontiers in Microbiology"},{"key":"bib87","doi-asserted-by":"publisher","first-page":"1183","DOI":"10.2147\/IDR.S161146","article-title":"Insertion element mediated mgrB disruption and presence of ISKpn28 in colistin-resistant Klebsiella pneumoniae isolates from Saudi Arabia","volume":"11","author":"Uz Zaman","year":"2018","journal-title":"Infection and Drug Resistance"},{"key":"bib88","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1007\/978-0-387-78885-2_5","article-title":"Small RNAs controlled by two-component systems","volume":"631","author":"Valverde","year":"2008","journal-title":"Advances in Experimental Medicine and Biology"},{"key":"bib89","doi-asserted-by":"publisher","first-page":"2661","DOI":"10.1111\/j.1742-4658.2007.05801.x","article-title":"Directed evolution of trimethoprim resistance in Escherichia coli","volume":"274","author":"Watson","year":"2007","journal-title":"The FEBS Journal"},{"key":"bib90","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-04059-1","article-title":"Evolution of high-level resistance during low-level antibiotic exposure","volume":"9","author":"Wistrand-Yuen","year":"2018","journal-title":"Nature Communications"},{"key":"bib91","doi-asserted-by":"publisher","first-page":"11863","DOI":"10.1073\/pnas.0804739105","article-title":"Accumulation of mutants in \u201caging\u201d bacterial colonies is due to growth under selection, not stress-induced mutagenesis","volume":"105","author":"Wrande","year":"2008","journal-title":"PNAS"},{"key":"bib92","doi-asserted-by":"publisher","DOI":"10.1093\/femsle\/fnz123","article-title":"MGRB affects the acid stress response of Escherichia coli by modulating the expression of iram","volume":"366","author":"Xu","year":"2019","journal-title":"FEMS Microbiology Letters"},{"key":"bib93","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-15350-5","article-title":"An acid-tolerance response system protecting exponentially growing Escherichia coli","volume":"11","author":"Xu","year":"2020","journal-title":"Nature Communications"},{"key":"bib94","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms12340","article-title":"Antimicrobial peptides trigger a division block in Escherichia coli through stimulation of a signalling system","volume":"7","author":"Yadavalli","year":"2016","journal-title":"Nature Communications"},{"key":"bib95","doi-asserted-by":"publisher","DOI":"10.1128\/JB.00305-20","article-title":"Functional determinants of a small protein controlling a broadly conserved bacterial sensor kinase","volume":"10","author":"Yadavalli","year":"2020","journal-title":"Journal of Bacteriology"},{"key":"bib96","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1046\/j.1365-2958.2002.03017.x","article-title":"Novel mode of transcription regulation of divergently overlapping promoters by PHOP, the regulator of two-component system sensing external magnesium availability","volume":"45","author":"Yamamoto","year":"2002","journal-title":"Molecular Microbiology"},{"key":"bib97","doi-asserted-by":"publisher","DOI":"10.1038\/msb.2009.92","article-title":"Update on the Keio collection of Escherichia coli single-gene deletion mutants","volume":"5","author":"Yamamoto","year":"2009","journal-title":"Molecular Systems Biology"},{"key":"bib98","doi-asserted-by":"publisher","first-page":"6080","DOI":"10.1128\/JB.00482-07","article-title":"FOLA, a new member of the tyrr regulon in Escherichia coli k-12","volume":"189","author":"Yang","year":"2007","journal-title":"Journal of Bacteriology"},{"key":"bib99","doi-asserted-by":"publisher","first-page":"E10792","DOI":"10.1073\/pnas.1717272114","article-title":"Osmosensing by the bacterial PHOQ\/PHOP two-component system","volume":"114","author":"Yuan","year":"2017","journal-title":"PNAS"},{"key":"bib100","doi-asserted-by":"publisher","first-page":"517","DOI":"10.1086\/315708","article-title":"Selection of antibiotic-resistant bacterial mutants: Allelic diversity among fluoroquinolone-resistant mutations","volume":"182","author":"Zhou","year":"2000","journal-title":"The Journal of Infectious Diseases"}],"container-title":["eLife"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/cdn.elifesciences.org\/articles\/70931\/elife-70931-v1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/cdn.elifesciences.org\/articles\/70931\/elife-70931-v1.xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/elifesciences.org\/articles\/70931","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,11]],"date-time":"2023-10-11T21:20:29Z","timestamp":1697059229000},"score":1,"resource":{"primary":{"URL":"https:\/\/elifesciences.org\/articles\/70931"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,30]]},"references-count":100,"alternative-id":["10.7554\/eLife.70931"],"URL":"https:\/\/doi.org\/10.7554\/elife.70931","archive":["CLOCKSS"],"relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2021.08.31.458319","asserted-by":"subject"},{"id-type":"doi","id":"10.1101\/2021.08.31.458319","asserted-by":"object"}],"is-supplemented-by":[{"id-type":"accession","id":"PRJNA741586","asserted-by":"subject"}],"has-review":[{"id-type":"doi","id":"10.7554\/eLife.70931.sa2","asserted-by":"object"},{"id-type":"doi","id":"10.7554\/eLife.70931.sa1","asserted-by":"object"}]},"ISSN":["2050-084X"],"issn-type":[{"value":"2050-084X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,30]]},"assertion":[{"value":"single anonymised","name":"peer_review_transparency","label":"Peer review transparency","group":{"name":"peer_review_taxonomy"}},{"value":"other reviewer(s), editor","name":"peer_review_interaction","label":"Peer review interaction","group":{"name":"peer_review_taxonomy"}},{"value":"review summaries, review reports, author\/editor communication, reviewer identities reviewer opt in, editor identities","name":"peer_review_published","label":"Peer review published","group":{"name":"peer_review_taxonomy"}},{"value":"open (sign in with ORCID iD required)","name":"post_publication_commenting","label":"Post publication commenting","group":{"name":"post_publication_commenting"}}],"article-number":"e70931"}}