{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T07:47:55Z","timestamp":1782460075937,"version":"3.54.5"},"reference-count":71,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,9,27]],"date-time":"2021-09-27T00:00:00Z","timestamp":1632700800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002367","name":"Chinese Academy of Sciences","doi-asserted-by":"publisher","award":["XDB29020000"],"award-info":[{"award-number":["XDB29020000"]}],"id":[{"id":"10.13039\/501100002367","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Microbiol."],"abstract":"<jats:p>Folates are required for the <jats:italic>de novo<\/jats:italic> biosynthesis of purines, thymine, methionine, glycine, and pantothenic acid, key metabolites that bacterial cells cannot survive without. Sulfonamides, which inhibit bacterial folate biosynthesis and are generally considered as bacteriostats, have been extensively used as broad-spectrum antimicrobials for decades. Here we show that, deleting <jats:italic>relA<\/jats:italic> in <jats:italic>Escherichia coli<\/jats:italic> and other bacterial species converted sulfamethoxazole from a bacteriostat into a bactericide. Not as previously assumed, the bactericidal effect of SMX was not caused by thymine deficiency. When <jats:italic>E. coli<\/jats:italic> \u2206<jats:italic>relA<\/jats:italic> was treated with SMX, reactive oxygen species and ferrous ion accumulated inside the bacterial cells, which caused extensive DNA double-strand breaks without the involvement of incomplete base excision repair. In addition, sulfamethoxazole showed bactericidal effect against <jats:italic>E. coli<\/jats:italic> O157 \u2206<jats:italic>relA<\/jats:italic> in mice, suggesting the possibility of designing new potentiators for sulfonamides targeting RelA. Thus, our study uncovered the previously unknown bactericidal effects of sulfonamides, which advances our understanding of their mechanisms of action, and will facilitate the designing of new potentiators for them.<\/jats:p>","DOI":"10.3389\/fmicb.2021.698468","type":"journal-article","created":{"date-parts":[[2021,9,27]],"date-time":"2021-09-27T17:40:22Z","timestamp":1632764422000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["relA Inactivation Converts Sulfonamides Into Bactericidal Compounds"],"prefix":"10.3389","volume":"12","author":[{"given":"Lizhen","family":"Si","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Gu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mi","family":"Wen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruiqi","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joy","family":"Fleming","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinyue","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jintian","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lijun","family":"Bi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaoyu","family":"Deng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,9,27]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"2248","DOI":"10.1128\/jb.01726-08","article-title":"The molecular alarmone (p)ppGpp mediates stress responses, vancomycin tolerance, and virulence in enterococcus faecalis","volume":"191","author":"Abranches","year":"2009","journal-title":"J. Bacteriol."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1146\/annurev.micro.52.1.591","article-title":"Thymine metabolism and thymineless death in prokaryotes and eukaryotes","volume":"52","author":"Ahmad","year":"1998","journal-title":"Annu. Rev. Microbiol."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"288","DOI":"10.1128\/AAC.21.2.288","article-title":"Bactericidal activity of trimethoprim alone and in combination with sulfamethoxazole on susceptible and resistant Escherichia coli k-12","volume":"21","author":"Amyes","year":"1982","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"e23479","DOI":"10.1371\/journal.pone.0023479","article-title":"The RelA\/SpoT homolog (RSH) superfamily: distribution and functional evolution of ppGpp synthetases and hydrolases across the tree of life","volume":"6","author":"Atkinson","year":"2011","journal-title":"PLoS One"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"e1005799","DOI":"10.1371\/journal.pgen.1005799","article-title":"RecG directs DNA synthesis during double-strand break repair","volume":"12","author":"Azeroglu","year":"2016","journal-title":"PLoS Genet."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"16738554","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":"Mol. Syst. Biol."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1016\/j.jpha.2015.11.005","article-title":"Methods for in vitro evaluating antimicrobial activity: a review","volume":"6","author":"Balouiri","year":"2016","journal-title":"J. Pharm. Anal."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"3007","DOI":"10.1099\/00221287-148-10-3007","article-title":"Specialized transduction: an efficient method for generating marked and unmarked targeted gene disruptions in Mycobacterium tuberculosis, M. bovis BCG and M. smegmatis","volume":"148","author":"Bardarov","year":"2002","journal-title":"Microbiology"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"350","DOI":"10.1128\/jb.74.3.350-355.1957","article-title":"The isolation and properties of amino acid requiring mutants of a thymineless bacterium","volume":"74","author":"Barner","year":"1957","journal-title":"J. Bacteriol."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"5510","DOI":"10.1128\/Jb.00562-09","article-title":"Respiration of Escherichia coli can be fully uncoupled via the nonelectrogenic terminal cytochrome bd-II oxidase","volume":"191","author":"Bekker","year":"2009","journal-title":"J. Bacteriol."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"637","DOI":"10.1002\/bies.10114","article-title":"The folic acid biosynthesis pathway in bacteria: evaluation of potential for antibacterial drug discovery","volume":"24","author":"Bermingham","year":"2002","journal-title":"BioEssays"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"320","DOI":"10.1038\/nrmicro.2016.34","article-title":"Distinguishing between resistance, tolerance and persistence to antibiotic treatment","volume":"14","author":"Brauner","year":"2016","journal-title":"Nat. Rev. Microbiol."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"160","DOI":"10.1016\/s1369-5274(00)00182-x","article-title":"Revisiting the stringent response, ppGpp and starvation signaling","volume":"4","author":"Chatterji","year":"2001","journal-title":"Curr. Opin. Microbiol."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"588","DOI":"10.1128\/jb.71.5.588-597.1956","article-title":"Studies on the induction of thymine deficiency and on the effects of thymine and thymidine analogues in Escherichia coli","volume":"71","author":"Cohen","year":"1956","journal-title":"J. Bacteriol."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"E1710","DOI":"10.1073\/pnas.1522179113","article-title":"ppGpp negatively impacts ribosome assembly affecting growth and antimicrobial tolerance in Gram-positive bacteria","volume":"113","author":"Corrigan","year":"2016","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"691","DOI":"10.1139\/cjb-78-6-691","article-title":"The fascinating world of folate and one-carbon metabolism","volume":"78","author":"Cossins","year":"2000","journal-title":"Can. J. Bot."},{"key":"ref17","first-page":"311","article-title":"Recombinational DNA repair in bacteria and the RecA protein","volume-title":"Progress in Nucleic Acid Research and Molecular Biology.","author":"Cox","year":"2000"},{"key":"ref18","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":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1667\/Rr2332.1","article-title":"Base damage immediately upstream from double-strand break ends is a more severe impediment to nonhomologous end joining than blocked 3\u2032-termini","volume":"175","author":"Datta","year":"2011","journal-title":"Radiat. Res."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"1102","DOI":"10.1016\/S0891-5849(02)00826-2","article-title":"Free radical-induced damage to DNA: mechanisms and measurement","volume":"32","author":"Dizdaroglu","year":"2002","journal-title":"Free Radic. Biol. Med."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"eaav2104","DOI":"10.1126\/sciadv.aav2104","article-title":"Inhibiting the stringent response blocks mycobacterium tuberculosis entry into quiescence and reduces persistence","volume":"5","author":"Dutta","year":"2019","journal-title":"Sci. Adv."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"E2100","DOI":"10.1073\/pnas.1401876111","article-title":"Antibiotics induce redox-related physiological alterations as part of their lethality","volume":"111","author":"Dwyer","year":"2014","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"482","DOI":"10.1016\/j.mib.2009.06.018","article-title":"Role of reactive oxygen species in antibiotic action and resistance","volume":"12","author":"Dwyer","year":"2009","journal-title":"Curr. Opin. Microbiol."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"22369","DOI":"10.1016\/S0021-9258(18)41538-4","article-title":"The inactivation of Fe-S cluster containing hydrolyases by superoxide","volume":"268","author":"Flint","year":"1993","journal-title":"J. Biol. Chem."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1126\/science.1219192","article-title":"Oxidation of the guanine nucleotide pool underlies cell death by bactericidal antibiotics","volume":"336","author":"Foti","year":"2012","journal-title":"Science"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"218","DOI":"10.1353\/bhm.0.0197","article-title":"The first miracle drugs: how the sulfa drugs transformed medicine","volume":"83","author":"Gaudilliere","year":"2009","journal-title":"Bull. Hist. Med."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"11512","DOI":"10.1073\/pnas.1706236114","article-title":"Maladaptive DNA repair is the ultimate contributor to the death of trimethoprim-treated cells under aerobic and anaerobic conditions","volume":"114","author":"Giroux","year":"2017","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"ref28","first-page":"430","article-title":"Potentiation of sulfonamides and antibiotics by trimethoprim [2,4-diamino-5-(3,4,5-trimethoxybenzyl) pyrimidine]","volume":"6","author":"Grunberg","year":"1966","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"119","DOI":"10.3109\/10715769009148579","article-title":"Superoxide-dependent formation of hydroxyl radicals from ferric-complexes and hydrogen peroxide: an evaluation of fourteen iron chelators","volume":"9","author":"Gutteridge","year":"1990","journal-title":"Free Radic. Res. Commun."},{"key":"ref30","first-page":"260","article-title":"Membrane-associated folate transport proteins","volume-title":"Methods in Enzymology,","author":"Henderson","year":"1986"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"11","DOI":"10.3389\/fmicb.2018.02138","article-title":"Escherichia coli cells exposed to lethal doses of electron beam irradiation retain their ability to propagate bacteriophages and are metabolically active","volume":"9","author":"Hieke","year":"2018","journal-title":"Front. Microbiol."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"e02124","DOI":"10.1128\/mBio.02124-16","article-title":"RelA mutant enterococcus faecium with multiantibiotic tolerance arising in an immunocompromised host","volume":"8","author":"Honsa","year":"2017","journal-title":"MBio"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1146\/annurev.micro.57.030502.090938","article-title":"Pathways of oxidative damage","volume":"57","author":"Imlay","year":"2003","journal-title":"Annu. Rev. Microbiol."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"640","DOI":"10.1126\/science.2834821","article-title":"Toxic DNA damage by hydrogen peroxide through the fenton reaction in vivo and in vitro","volume":"240","author":"Imlay","year":"1988","journal-title":"Science"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"6957","DOI":"10.1016\/S0021-9258(20)89596-9","article-title":"Assay of metabolic superoxide production in Escherichia coli","volume":"266","author":"Imlay","year":"1991","journal-title":"J. Biol. Chem."},{"key":"ref36","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1007\/s12038-012-9218-2","article-title":"DNA damage by reactive species: mechanisms, mutation and repair","volume":"37","author":"Jena","year":"2012","journal-title":"J. Biosci."},{"key":"ref37","first-page":"247","article-title":"Thymineless death lives on: new insights into a classic phenomenon","volume-title":"Annual Review of Microbiology.","author":"Khodursky","year":"2015"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"5679","DOI":"10.1074\/jbc.RA117.000383","article-title":"Guanosine tetra- and pentaphosphate increase antibiotic tolerance by reducing reactive oxygen species production in Vibrio cholerae","volume":"293","author":"Kim","year":"2018","journal-title":"J. Biol. Chem."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1016\/0300-9084(93)90029-R","article-title":"Requirement of homologous recombination functions for viability of the Escherichia-coli cell that lacks rnase-Hi and exonuclease-V activities","volume":"75","author":"Kogoma","year":"1993","journal-title":"Biochimie"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"797","DOI":"10.1016\/j.cell.2007.06.049","article-title":"A common mechanism of cellular death induced by bactericidal antibiotics","volume":"130","author":"Kohanski","year":"2007","journal-title":"Cell"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"679","DOI":"10.1016\/j.cell.2008.09.038","article-title":"Mistranslation of membrane proteins and two-component system activation trigger antibiotic-mediated cell death","volume":"135","author":"Kohanski","year":"2008","journal-title":"Cell"},{"key":"ref42","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1021\/cr0301144","article-title":"DNA and RNA synthesis: antifolates","volume":"105","author":"Kompis","year":"2005","journal-title":"Chem. Rev."},{"key":"ref43","doi-asserted-by":"publisher","first-page":"619","DOI":"10.1111\/j.1365-2443.2010.01405.x","article-title":"Stalled replication fork repair and misrepair during thymineless death in Escherichia coli","volume":"15","author":"Kuong","year":"2010","journal-title":"Genes Cells"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"8173","DOI":"10.1073\/pnas.1509743112","article-title":"Antibiotic efficacy is linked to bacterial cellular respiration","volume":"112","author":"Lobritz","year":"2015","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"ref45","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1385\/Cbb:35:2:141","article-title":"Repair of oxidative DNA damage \u2013 mechanisms and functions","volume":"35","author":"Lu","year":"2001","journal-title":"Cell Biochem. Biophys."},{"key":"ref46","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1016\/j.dnarep.2016.03.012","article-title":"Prompt repair of hydrogen peroxide-induced DNA lesions prevents catastrophic chromosomal fragmentation","volume":"41","author":"Mahaseth","year":"2016","journal-title":"DNA Repair"},{"key":"ref47","doi-asserted-by":"publisher","first-page":"2949","DOI":"10.1038\/s41467-021-23191-z","article-title":"A trimethoprim derivative impedes antibiotic resistance evolution","volume":"12","author":"Manna","year":"2021","journal-title":"Nat. Commun."},{"key":"ref48","doi-asserted-by":"publisher","first-page":"130","DOI":"10.1056\/NEJM198201213060302","article-title":"Emergence of high-level trimethoprim resistance in fecal Escherichia coli during oral administration of trimethoprim or trimethoprim-sulfamethoxazole","volume":"306","author":"Murray","year":"1982","journal-title":"N. Engl. J. Med."},{"key":"ref49","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1016\/j.bbabio.2015.11.005","article-title":"ATP synthase from Escherichia coli: mechanism of rotational catalysis, and inhibition with the \u03b5 subunit and phytopolyphenols","volume":"1857","author":"Nakanishi-Matsui","year":"2016","journal-title":"Biochim. Biophys. Acta"},{"key":"ref50","doi-asserted-by":"publisher","first-page":"491","DOI":"10.1021\/tx0600043","article-title":"Mechanisms of formation, genotoxicity, and mutation of guanine oxidation products","volume":"19","author":"Neeley","year":"2006","journal-title":"Chem. Res. Toxicol."},{"key":"ref51","doi-asserted-by":"publisher","first-page":"982","DOI":"10.1126\/science.1211037","article-title":"Active starvation pesponses mediate antibiotic tolerance in biofilms and nutrient-limited bacteria","volume":"334","author":"Nguyen","year":"2011","journal-title":"Science"},{"key":"ref52","doi-asserted-by":"publisher","first-page":"762","DOI":"10.3389\/fmicb.2019.00762","article-title":"Impact of ROS-induced damage of TCA cycle enzymes on metabolism and virulence of Salmonella enterica serovar Typhimurium","volume":"10","author":"Noster","year":"2019","journal-title":"Front. Microbiol."},{"key":"ref53","doi-asserted-by":"publisher","first-page":"864","DOI":"10.1086\/381972","article-title":"Clinical relevance of bacteriostatic versus bactericidal mechanisms of action in the treatment of gram-positive bacterial infections","volume":"38","author":"Pankey","year":"2004","journal-title":"Clin. Infect. Dis."},{"key":"ref54","doi-asserted-by":"publisher","first-page":"563","DOI":"10.1111\/j.1462-2920.2010.02357.x","article-title":"ppGpp is the major source of growth rate control in E. coli","volume":"13","author":"Potrykus","year":"2011","journal-title":"Environ. Microbiol."},{"key":"ref55","doi-asserted-by":"publisher","first-page":"7094","DOI":"10.1016\/S0021-9258(19)68927-1","article-title":"Hydrogen peroxide kills Staphylococcus aureus by reacting with staphylococcal iron to form hydroxyl radical","volume":"256","author":"Repine","year":"1981","journal-title":"J. Biol. Chem."},{"key":"ref56","doi-asserted-by":"publisher","first-page":"e15","DOI":"10.1371\/journal.pgen.0010015","article-title":"Comparative and evolutionary analysis of the bacterial homologous recombination systems","volume":"1","author":"Rocha","year":"2005","journal-title":"PLoS Genet."},{"key":"ref57","doi-asserted-by":"publisher","first-page":"e0008913","DOI":"10.1371\/journal.pntd.0008913","article-title":"Genomic and RT-qPCR analysis of trimethoprim-sulfamethoxazole and meropenem resistance in Burkholderia pseudomallei clinical isolates","volume":"15","author":"Schnetterle","year":"2021","journal-title":"PLoS Negl. Trop. Dis."},{"key":"ref58","doi-asserted-by":"publisher","first-page":"1455","DOI":"10.1002\/jps.2600570902","article-title":"Sulfonamides, structure-activity relationship, and mode of action: structural problems of the antibacterial action of 4-aminobenzoic acid (PABA) antagonists","volume":"57","author":"Seydel","year":"1968","journal-title":"J. Pharm. Sci."},{"key":"ref59","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1016\/S0027-5107(99)00124-4","article-title":"Visual quantification of DNA double-strand breaks in bacteria","volume":"429","author":"Singh","year":"1999","journal-title":"Mutat. Res."},{"key":"ref60","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1016\/j.mimet.2012.08.009","article-title":"Adaptation of the neutral bacterial comet assay to assess antimicrobial-mediated DNA double-strand breaks in Escherichia coli","volume":"91","author":"Solanky","year":"2012","journal-title":"J. Microbiol. Methods"},{"key":"ref61","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1016\/j.mib.2008.02.001","article-title":"Control of bacterial transcription, translation and replication by (p)ppGpp","volume":"11","author":"Srivatsan","year":"2008","journal-title":"Curr. Opin. Microbiol."},{"key":"ref62","doi-asserted-by":"publisher","first-page":"2185","DOI":"10.1016\/j.lfs.2004.08.037","article-title":"Selenoureas and thioureas are effective superoxide radical scavengers in vitro","volume":"76","author":"Takahashi","year":"2005","journal-title":"Life Sci."},{"key":"ref63","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1016\/j.tim.2017.11.006","article-title":"Antibiotic killing through incomplete DNA repair","volume":"26","author":"ter Kuile","year":"2018","journal-title":"Trends Microbiol."},{"key":"ref64","first-page":"483","article-title":"Role of thymidine for the activity of trimethoprim, sulfonamides and their combinations","volume":"247","author":"Then","year":"1980","journal-title":"Zentralbl. Bakteriol. A"},{"key":"ref65","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1099\/00221287-76-2-255","article-title":"Sulfonamide-induced thymineless death in Escherichia coli","volume":"76","author":"Then","year":"1973","journal-title":"J. Gen. Microbiol."},{"key":"ref66","doi-asserted-by":"publisher","first-page":"2261","DOI":"10.1021\/acsmedchemlett.0c00393","article-title":"Dual-target inhibitors of the Folate pathway inhibit intrinsically trimethoprim-resistant DfrB dihydrofolate reductases","volume":"11","author":"Toulouse","year":"2020","journal-title":"ACS Med. Chem. Lett."},{"key":"ref67","doi-asserted-by":"publisher","first-page":"461","DOI":"10.1128\/JB.183.2.461-467.2001","article-title":"Oxygen-and growth rate-dependent regulation of Escherichia coli fumarase (FumA, FumB, and FumC) activity","volume":"183","author":"Tseng","year":"2001","journal-title":"J. Bacteriol."},{"key":"ref68","doi-asserted-by":"publisher","first-page":"2461","DOI":"10.1016\/j.febslet.2013.06.019","article-title":"Elevated citrate levels in non-alcoholic fatty liver disease: the potential of citrate to promote radical production","volume":"587","author":"van de Wier","year":"2013","journal-title":"FEBS Lett."},{"key":"ref69","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1016\/S0021-9258(18)65874-0","article-title":"Acetylornithinase of Escherichia coli \u2013 partial purification and some properties","volume":"218","author":"Vogel","year":"1956","journal-title":"J. Biol. Chem."},{"key":"ref70","doi-asserted-by":"publisher","first-page":"714","DOI":"10.1007\/s13238-012-2051-4","article-title":"Glutathione regulates the transfer of iron-sulfur cluster from monothiol and dithiol glutaredoxins to apo ferredoxin","volume":"3","author":"Wang","year":"2012","journal-title":"Protein Cell"},{"key":"ref71","doi-asserted-by":"publisher","first-page":"735","DOI":"10.1016\/j.tim.2018.06.003","article-title":"Antibiotic scars left on the gut microbiota from the stringent response","volume":"26","author":"Yi","year":"2018","journal-title":"Trends Microbiol."}],"container-title":["Frontiers in Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2021.698468\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,27]],"date-time":"2021-09-27T17:40:29Z","timestamp":1632764429000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2021.698468\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,27]]},"references-count":71,"alternative-id":["10.3389\/fmicb.2021.698468"],"URL":"https:\/\/doi.org\/10.3389\/fmicb.2021.698468","relation":{},"ISSN":["1664-302X"],"issn-type":[{"value":"1664-302X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,27]]},"article-number":"698468"}}