{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T06:08:59Z","timestamp":1789711739487,"version":"4.0.1"},"reference-count":60,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T00:00:00Z","timestamp":1789689600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Microbiol."],"abstract":"<jats:p>\n                    Antibiotic resistance continues to grow as a public health problem. One of the reasons for this continued growth is that resistance to antibiotics is strongly selected for in the presence of antibiotics and weakly selected against after their removal. This is frequently thought to be due to the effects of compensatory mutations. However, compensatory mutations are often not found in clinically relevant strains of antibiotic resistant pathogens. Here, we conduct experiments\n                    <jats:italic>in vitro<\/jats:italic>\n                    using chemostats and serial transfer flasks that highlight the role that fine scale differences in environment play in the maintenance of populations after selection for resistance. Chemostat conditions resulted in a different set of mutations than in flasks, showing that the differences in the mode of growth are capable of reliably changing the force and direction of selection. Our results suggest that antibiotic resistance can make novel adaptive paths available to populations through newly arising variation, allowing populations to climb previously unavailable adaptive peaks in a manner similar to Wright\u2019s shifting balance, but driven only by selection.\n                  <\/jats:p>","DOI":"10.3389\/fmicb.2026.1905746","type":"journal-article","created":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T05:38:29Z","timestamp":1789709909000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Antibiotic resistance increases evolvability and maximizes opportunities across fitness landscapes"],"prefix":"10.3389","volume":"17","author":[{"given":"Fabrizio","family":"Spagnolo","sequence":"first","affiliation":[{"name":"Department of Natural and Life Sciences, Long Island University-Post","place":["Brookville, NY, United States"]},{"name":"Department of Ecology and Evolution, Stony Brook University","place":["Stony Brook, NY, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel E.","family":"Dykhuizen","sequence":"additional","affiliation":[{"name":"Department of Ecology and Evolution, Stony Brook University","place":["Stony Brook, NY, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,18]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.jmb.2011.04.068","article-title":"Error-prone and error-restrictive mutations affecting ribosomal protein S12","volume":"410","author":"Agarwal","year":"2011","journal-title":"J. Mol. Biol."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"569","DOI":"10.1093\/jac\/dks427","article-title":"Voluntary ban on cephalosporin use in Danish pig production has effectively reduced extended-spectrum cephalosporinase-producing Escherichia coli in slaughter pigs","volume":"68","author":"Agers\u00f8","year":"2013","journal-title":"J. Antimicrob. Chemother."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1016\/0022-2836(89)90509-3","article-title":"Mutations in ribosomal proteins S4 and S12 influence the higher order structure of 16 S ribosomal RNA","volume":"208","author":"Allen","year":"1989","journal-title":"J. Mol. Biol."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"467","DOI":"10.1007\/BF00332630","article-title":"Translation rates and misreading characteristics of rpsD mutants in Escherichia coli","volume":"187","author":"Andersson","year":"1982","journal-title":"Mol. Gen. Genet."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"260","DOI":"10.1038\/nrmicro2319","article-title":"Antibiotic resistance and its cost: is it possible to reverse resistance?","volume":"8","author":"Andersson","year":"2010","journal-title":"Nat. Rev. Microbiol."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1016\/S1369-5274(99)00005-3","article-title":"The biological cost of antibiotic resistance","volume":"2","author":"Andersson","year":"1999","journal-title":"Curr. Opin. Microbiol."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"1152","DOI":"10.1073\/pnas.96.3.1152","article-title":"The relationship between the volume of antimicrobial consumption in human communities and the frequency of resistace","volume":"96","author":"Austin","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"441","DOI":"10.1038\/s41579-019-0196-3","article-title":"Definitions and guidelines for research on antibiotic persistence","volume":"17","author":"Balaban","year":"2019","journal-title":"Nat. Rev. Microbiol."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"3949","DOI":"10.1073\/pnas.95.7.3949","article-title":"Virulence of antibiotic-resistant Salmonella typhimurium","volume":"95","author":"Bjorkman","year":"1998","journal-title":"Proc. Natl. Acad. Sci."},{"key":"ref10","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":"ref11","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1046\/j.1365-2958.1999.01142.x","article-title":"Novel ribosomal mutations affecting translational accuracy, antibiotic resistance and virulence of Salmonella typhimurium","volume":"31","author":"Bj\u00f6rkman","year":"1999","journal-title":"Mol. Microbiol."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1007\/BF00328706","article-title":"Kinetic impairment of restrictive streptomycin-resistant ribosomes","volume":"198","author":"Bohman","year":"1984","journal-title":"Mol. Gen. Genet."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"894","DOI":"10.1038\/nrmicro2693","article-title":"Tackling antibiotic resistance","volume":"9","author":"Bush","year":"2011","journal-title":"Nat. Rev. Microbiol."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/srep26717","article-title":"Phage selection restores antibiotic sensitivity in MDR Pseudomonas aeruginosa","volume":"6","author":"Chan","year":"2016","journal-title":"Sci. Rep."},{"key":"ref15","doi-asserted-by":"crossref","DOI":"10.1201\/9781003605942","volume-title":"Experimental Evolution: The Making of a Modern Science","author":"Dean","year":"2026"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"613","DOI":"10.1016\/0076-6879(93)24046-W","article-title":"Chemostats used for studying natural selection and adaptive evolution","volume":"224","author":"Dykhuizen","year":"1993","journal-title":"Methods Enzymol."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"801","DOI":"10.1093\/genetics\/96.4.801","article-title":"Selective neutrality of 6PGD allozymes in E. Coli and the effects of genetic background","volume":"96","author":"Dykhuizen","year":"1980","journal-title":"Genetics"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"3173","DOI":"10.1128\/JB.00128-15","article-title":"Acetate exposure determines the diauxic behavior of Escherichia coli during the glucose-acetate transition","volume":"197","author":"Enjalbert","year":"2015","journal-title":"J. Bacteriol."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1016\/j.tree.2018.10.009","article-title":"Evolution in the light of fitness landscape theory","volume":"34","author":"Fragata","year":"2019","journal-title":"Trends Ecol. Evol."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"32188","DOI":"10.1074\/jbc.M109.062745","article-title":"Ribosomal protein S12 and aminoglycoside antibiotics modulate A-site mRNA cleavage and transfer-messenger RNA activity in Escherichia coli","volume":"284","author":"Holberger","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"579","DOI":"10.1146\/annurev-micro-090816-093813","article-title":"Evolutionary trajectories to antibiotic resistance","volume":"71","author":"Hughes","year":"2017","journal-title":"Ann. Rev. Microbiol."},{"key":"ref22","doi-asserted-by":"publisher","DOI":"10.18637\/jss.v033.i07","article-title":"Grofit: fitting biological growth curves with R","volume":"33","author":"Kahm","year":"2010","journal-title":"J. Stat. Softw."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1146\/annurev.ge.26.120192.000333","article-title":"Translational accuracy and the fitness of bacteria","volume":"26","author":"Kurland","year":"1992","journal-title":"Annu. Rev. Genet."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"1315","DOI":"10.1086\/285289","article-title":"Long-term experimental evolution in Escherichia coli. I. Adaptation and divergence during 2,000 generations","volume":"138","author":"Lenski","year":"1991","journal-title":"Am. Nat."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"S9","DOI":"10.1093\/clinids\/24.Supplement_1.S9","article-title":"The population genetics of antibiotic resistance","volume":"24","author":"Levin","year":"1997","journal-title":"Clin. Infect. Dis."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"480","DOI":"10.1186\/s13054-014-0480-6","article-title":"Antibiotic stewardship in the intensive care unit","volume":"18","author":"Luyt","year":"2014","journal-title":"Crit. Care"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1093\/emph\/eou032","article-title":"Limits to compensatory adaptation and the persistence of antibiotic resistance in pathogenic bacteria","volume":"2015","author":"MacLean","year":"2015","journal-title":"Evolution, Medicine, and Public Health"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"360","DOI":"10.1016\/j.resmic.2004.01.019","article-title":"Adaptation to the deleterious effects of antimicrobial drug resistance mutations by compensatory evolution","volume":"155","author":"Maisnier-Patin","year":"2004","journal-title":"Res. Microbiol."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1046\/j.1365-2958.2002.03173.x","article-title":"Compensatory adaptation to the deleterious effect of antibiotic resistance in Salmonella typhimurium","volume":"46","author":"Maisnier-Patin","year":"2002","journal-title":"Mol. Microbiol."},{"key":"ref30","volume-title":"A Short Course in Bacterial Genetics: A Laboratory Manual and Handbook for Escherichia coli and Related Bacteria","author":"Miller","year":"1992"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"5373","DOI":"10.1128\/AAC.01473-13","article-title":"Adaptation of Enterococcus faecalis to daptomycin reveals an ordered progression to resistance","volume":"57","author":"Miller","year":"2013","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1016\/S1473-3099(08)70017-3","article-title":"Sustained reduction of antibiotic use and low bacterial resistance: 10-year follow-up of the Swedish Strama programme","volume":"8","author":"M\u00f6lstad","year":"2008","journal-title":"Lancet Infect. Dis."},{"key":"ref33","volume-title":"The Dynamics of Bacterial Populations Maintained in the Chemostat. Carnegie Institute publ. no. 614","author":"Moser","year":"1958"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1046\/j.1462-2920.1999.00002.x","article-title":"Adaptive mgl-regulatory mutations and genetic diversity evolving in glucose-limited Escherichia coli populations","volume":"1","author":"Notley-McRobb","year":"1999","journal-title":"Environ. Microbiol."},{"key":"ref35","doi-asserted-by":"publisher","first-page":"539","DOI":"10.1534\/genetics.109.106104","article-title":"The fitness cost of streptomycin resistance depends on rpsL mutation, carbon source and RpoS (sigmaS)","volume":"183","author":"Paulander","year":"2009","journal-title":"Genetics"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1038\/s41576-018-0069-z","article-title":"The causes of evolvability and their evolution","volume":"20","author":"Payne","year":"2019","journal-title":"Nat. Rev. Genet."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"870","DOI":"10.1038\/nrmicro1265","article-title":"The bacterial ribosome as a target for antibiotics","volume":"3","author":"Poehlsgaard","year":"2005","journal-title":"Nat. Rev. Microbiol."},{"key":"ref38","doi-asserted-by":"publisher","first-page":"1471","DOI":"10.1093\/genetics\/156.4.1471","article-title":"Compensatory evolution in rifampin-resistant Escherichia coli","volume":"156","author":"Reynolds","year":"2000","journal-title":"Genetics"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"230","DOI":"10.1016\/S0140-6736(70)90585-4","article-title":"Antibiotic-resistant Staphylococcus aureus and hospital antibiotic policies","volume":"295","author":"Ridley","year":"1970","journal-title":"Lancet"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1111\/j.1420-9101.2006.01255.x","article-title":"The evolution of trade-offs: where are we?","volume":"20","author":"Roff","year":"2007","journal-title":"J of Evolutionary Biology"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"1204","DOI":"10.1128\/AAC.46.5.1204-1211.2002","article-title":"Fitness cost of chromosomal drug resistance-conferring mutations","volume":"46","author":"Sander","year":"2002","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref42","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1038\/381120b0","article-title":"Reducing antibiotic resistance","volume":"381","author":"Schrag","year":"1996","journal-title":"Nature"},{"key":"ref43","doi-asserted-by":"publisher","first-page":"1287","DOI":"10.1098\/rspb.1997.0178","article-title":"Adaptation to the fitness costs of antibiotic resistance in Escherichia coli","volume":"264","author":"Schrag","year":"1997","journal-title":"Proc. Biolo. Sci."},{"key":"ref44","doi-asserted-by":"publisher","first-page":"441","DOI":"10.1056\/NEJM199708143370701","article-title":"The effect of changes in the consumption of macrolide antibiotics on erythomycin resistance in group a streptococci in Finland","volume":"337","author":"Seppala","year":"1997","journal-title":"N. Engl. J. Med."},{"key":"ref45","doi-asserted-by":"publisher","first-page":"163","DOI":"10.2144\/0000113924","article-title":"Streamlined extract preparation for Escherichia coli-based cell-free protein synthesis by sonication or bead vortex mixing","volume":"53","author":"Shrestha","year":"2012","journal-title":"BioTechniques"},{"key":"ref46","doi-asserted-by":"publisher","first-page":"628","DOI":"10.1038\/258628a0","article-title":"Persistence of tetracycline resistance in pig E. coli","volume":"258","author":"Smith","year":"1975","journal-title":"Nature"},{"key":"ref47","volume-title":"Biometry","author":"Sokal","year":"1995"},{"key":"ref48","doi-asserted-by":"publisher","first-page":"1336","DOI":"10.1128\/AAC.01359-15","article-title":"The evolution of resistance to continuously increasing streptomycin concentrations in populations of E. coli","volume":"60","author":"Spagnolo","year":"2016","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref49","doi-asserted-by":"publisher","first-page":"e1001935","DOI":"10.1371\/journal.pbio.1001935","article-title":"The genomic landscape of compensatory evolution","volume":"12","author":"Szamecz","year":"2014","journal-title":"PLoS Biol."},{"key":"ref50","doi-asserted-by":"publisher","first-page":"W345","DOI":"10.1093\/nar\/gkac247","article-title":"The galaxy platform for accessible, reproducible and collaborative biomedical analyses: 2022 update","volume":"50","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"ref51","volume-title":"Tackling Drug-Resistant Infections Globally: Final Report and Recommendations","year":"2016"},{"key":"ref52","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":"Nat. Genet."},{"key":"ref53","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1093\/jac\/46.1.146","article-title":"The effect of banning avoparcin on VRE carriage in the Netherlands","volume":"46","author":"van den Bogaard","year":"2000","journal-title":"J. Antimicrob. Chemother."},{"key":"ref54","doi-asserted-by":"publisher","first-page":"967","DOI":"10.1111\/j.1558-5646.1996.tb02339.x","article-title":"Complex adaptations and the evolution of evolvability","volume":"50","author":"Wagner","year":"1996","journal-title":"Evolution"},{"key":"ref55","doi-asserted-by":"publisher","first-page":"5296","DOI":"10.1002\/ece3.3096","article-title":"Evolutionary implications of Liebig\u2019s law of the minimum: selection under low concentrations of two nonsubstitutable nutrients","volume":"7","author":"Warsi","year":"2017","journal-title":"Ecol. Evol."},{"key":"ref56","doi-asserted-by":"publisher","first-page":"1599","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":"Nat. Commun."},{"key":"ref57","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1093\/genetics\/16.2.97","article-title":"EVOLUTION IN MENDELIAN POPULATIONS","volume":"16","author":"Wright","year":"1931","journal-title":"Genetics"},{"key":"ref58","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1086\/281903","article-title":"Modes of selection","volume":"90","author":"Wright","year":"1956","journal-title":"Am. Nat."},{"key":"ref59","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1146\/annurev.ge.16.120182.000245","article-title":"The shifting balance theory and macroevolution","volume":"16","author":"Wright","year":"1982","journal-title":"Annu. Rev. Genet."},{"key":"ref60","doi-asserted-by":"publisher","first-page":"e2997","DOI":"10.7717\/peerj.2997","article-title":"Variant profiling of evolving prokaryotic populations","volume":"5","author":"Zojer","year":"2017","journal-title":"PeerJ"}],"container-title":["Frontiers in Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2026.1905746\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T05:38:31Z","timestamp":1789709911000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2026.1905746\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,18]]},"references-count":60,"alternative-id":["10.3389\/fmicb.2026.1905746"],"URL":"https:\/\/doi.org\/10.3389\/fmicb.2026.1905746","relation":{},"ISSN":["1664-302X"],"issn-type":[{"value":"1664-302X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,18]]},"article-number":"1905746"}}