{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T22:46:16Z","timestamp":1793400376179,"version":"4.5.0"},"reference-count":86,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,12,2]],"date-time":"2024-12-02T00:00:00Z","timestamp":1733097600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,12,2]],"date-time":"2024-12-02T00:00:00Z","timestamp":1733097600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"European Research Council"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Microbiol"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    By acquiring or evolving resistance to one antibiotic, bacteria can become cross-resistant to a second antibiotic, which further limits therapeutic choices. In the opposite scenario, initial resistance leads to collateral sensitivity to a second antibiotic, which can inform cycling or combinatorial treatments. Despite their clinical relevance, our knowledge of both interactions is limited. We used published chemical genetics data of the\n                    <jats:italic>Escherichia coli<\/jats:italic>\n                    single-gene deletion library in 40 antibiotics and devised a metric that discriminates between known cross-resistance and collateral-sensitivity antibiotic interactions. Thereby we inferred 404 cases of cross-resistance and 267 of collateral-sensitivity, expanding the number of known interactions by over threefold. We further validated 64\/70 inferred interactions using experimental evolution. By identifying mutants driving these interactions in chemical genetics, we demonstrated that a drug pair can exhibit both interactions depending on the resistance mechanism. Finally, we applied collateral-sensitive drug pairs in combination to reduce antibiotic-resistance development in vitro.\n                  <\/jats:p>","DOI":"10.1038\/s41564-024-01857-w","type":"journal-article","created":{"date-parts":[[2024,12,2]],"date-time":"2024-12-02T05:01:56Z","timestamp":1733115716000},"page":"202-216","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["Systematic mapping of antibiotic cross-resistance and collateral sensitivity with chemical genetics"],"prefix":"10.1038","volume":"10","author":[{"given":"Nazgul","family":"Sakenova","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8239-0353","authenticated-orcid":false,"given":"Elisabetta","family":"Cacace","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6823-5269","authenticated-orcid":false,"given":"Askarbek","family":"Orakov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian","family":"Huber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6900-6986","authenticated-orcid":false,"given":"Vallo","family":"Varik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1434-5176","authenticated-orcid":false,"given":"George","family":"Kritikos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3043-3259","authenticated-orcid":false,"given":"Jan","family":"Michiels","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peer","family":"Bork","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pascale","family":"Cossart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5564-1644","authenticated-orcid":false,"given":"Camille V.","family":"Goemans","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0797-9018","authenticated-orcid":false,"given":"Athanasios","family":"Typas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,12,2]]},"reference":[{"key":"1857_CR1","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1016\/S0140-6736(21)02724-0","volume":"399","author":"CJL Murray","year":"2022","unstructured":"Murray, C. J. L. et al. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Lancet 399, 629\u2013655 (2022).","journal-title":"Lancet"},{"key":"1857_CR2","doi-asserted-by":"publisher","first-page":"e40","DOI":"10.1016\/S1473-3099(18)30513-9","volume":"19","author":"U Theuretzbacher","year":"2019","unstructured":"Theuretzbacher, U. et al. Analysis of the clinical antibacterial and antituberculosis pipeline. Lancet Infect. Dis. 19, e40\u2013e50 (2019).","journal-title":"Lancet Infect. Dis."},{"key":"1857_CR3","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1038\/s41429-023-00629-8","volume":"76","author":"MS Butler","year":"2023","unstructured":"Butler, M. S., Henderson, I. R., Capon, R. J. & Blaskovich, M. A. T. Antibiotics in the clinical pipeline as of December 2022. J. Antibiot. 76, 431\u2013473 (2023).","journal-title":"J. Antibiot."},{"key":"1857_CR4","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1128\/jb.64.4.489-499.1952","volume":"64","author":"W Szybalski","year":"1952","unstructured":"Szybalski, W. & Bryson, V. Genetic studies on microbial cross-resistance to toxic agents I: cross resistance of Escherichia coli to fifteen antibiotics. J. Bacteriol. 64, 489\u2013499 (1952).","journal-title":"J. Bacteriol."},{"key":"1857_CR5","first-page":"712","volume":"88","author":"EH Beutner","year":"1963","unstructured":"Beutner, E. H., Doyle, W. M. & Evander, L. C. Collateral susceptibility of isoniazid-resistant tubercle bacilli to nitrofurans. Am. Rev. Respiratory Dis. 88, 712\u2013715 (1963).","journal-title":"Am. Rev. Respiratory Dis."},{"key":"1857_CR6","doi-asserted-by":"publisher","first-page":"aad3292","DOI":"10.1126\/science.aad3292","volume":"351","author":"M Baym","year":"2016","unstructured":"Baym, M., Stone, L. K. & Kishony, R. Multidrug evolutionary strategies to reverse antibiotic resistance. Science 351, aad3292 (2016).","journal-title":"Science"},{"key":"1857_CR7","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.3000612","volume":"18","author":"R Roemhild","year":"2020","unstructured":"Roemhild, R., Linkevicius, M. & Andersson, D. I. Molecular mechanisms of collateral sensitivity to the antibiotic nitrofurantoin. PLoS Biol. 18, e3000612 (2020).","journal-title":"PLoS Biol."},{"key":"1857_CR8","doi-asserted-by":"publisher","first-page":"204ra132","DOI":"10.1126\/scitranslmed.3006609","volume":"5","author":"L Imamovic","year":"2013","unstructured":"Imamovic, L. & Sommer, M. O. A. Use of collateral sensitivity networks to design drug cycling protocols that avoid resistance development. Sci. Transl. Med. 5, 204ra132 (2013).","journal-title":"Sci. Transl. Med."},{"key":"1857_CR9","doi-asserted-by":"publisher","first-page":"14494","DOI":"10.1073\/pnas.1409800111","volume":"111","author":"S Kim","year":"2014","unstructured":"Kim, S., Lieberman, T. D. & Kishony, R. Alternating antibiotic treatments constrain evolutionary paths to multidrug resistance. Proc. Natl Acad. Sci. USA 111, 14494\u201314499 (2014).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"1857_CR10","doi-asserted-by":"publisher","first-page":"e2004356","DOI":"10.1371\/journal.pbio.2004356","volume":"16","author":"C Barbosa","year":"2018","unstructured":"Barbosa, C., Beardmore, R., Schulenburg, H. & Jansen, G. Antibiotic combination efficacy (ACE) networks for a Pseudomonas aeruginosa model. PLoS Biol. 16, e2004356 (2018).","journal-title":"PLoS Biol."},{"key":"1857_CR11","doi-asserted-by":"publisher","first-page":"9767","DOI":"10.1073\/pnas.1810004115","volume":"115","author":"R Roemhild","year":"2018","unstructured":"Roemhild, R. et al. Cellular hysteresis as a principle to maximize the efficacy of antibiotic therapy. Proc. Natl Acad. Sci. USA 115, 9767\u20139772 (2018).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"1857_CR12","doi-asserted-by":"publisher","first-page":"eaba5493","DOI":"10.1126\/sciadv.aba5493","volume":"6","author":"S Hernando-Amado","year":"2020","unstructured":"Hernando-Amado, S., Sanz-Garc\u00eda, F. & Mart\u00ednez, J. L. Rapid and robust evolution of collateral sensitivity in Pseudomonas aeruginosa antibiotic-resistant mutants. Sci. Adv. 6, eaba5493 (2020).","journal-title":"Sci. Adv."},{"key":"1857_CR13","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-25927-3","volume":"12","author":"LBS Aulin","year":"2021","unstructured":"Aulin, L. B. S., Liakopoulos, A., van der Graaf, P. H., Rozen, D. E. & van Hasselt, J. G. C. Design principles of collateral sensitivity-based dosing strategies. Nat. Commun. 12, 5691 (2021).","journal-title":"Nat. Commun."},{"key":"1857_CR14","doi-asserted-by":"publisher","first-page":"2057","DOI":"10.1093\/molbev\/msab006","volume":"38","author":"LJ Jahn","year":"2021","unstructured":"Jahn, L. J. et al. Compatibility of evolutionary responses to constituent antibiotics drive resistance evolution to drug pairs. Mol. Biol. Evol. 38, 2057\u20132069 (2021).","journal-title":"Mol. Biol. Evol."},{"key":"1857_CR15","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-37357-4","volume":"14","author":"S Hernando-Amado","year":"2023","unstructured":"Hernando-Amado, S., Laborda, P. & Mart\u00ednez, J. L. Tackling antibiotic resistance by inducing transient and robust collateral sensitivity. Nat. Commun. 14, 1723 (2023).","journal-title":"Nat. Commun."},{"key":"1857_CR16","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.51481","volume":"8","author":"C Barbosa","year":"2019","unstructured":"Barbosa, C., R\u00f6mhild, R., Rosenstiel, P. & Schulenburg, H. Evolutionary stability of collateral sensitivity to antibiotics in the model pathogen Pseudomonas aeruginosa. eLife 8, e51481 (2019).","journal-title":"eLife"},{"key":"1857_CR17","doi-asserted-by":"publisher","first-page":"700","DOI":"10.1038\/msb.2013.57","volume":"9","author":"V L\u00e1z\u00e1r","year":"2013","unstructured":"L\u00e1z\u00e1r, V. et al. Bacterial evolution of antibiotic hypersensitivity. Mol. Syst. Biol. 9, 700 (2013).","journal-title":"Mol. Syst. Biol."},{"key":"1857_CR18","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms5352","volume":"5","author":"V L\u00e1z\u00e1r","year":"2014","unstructured":"L\u00e1z\u00e1r, V. et al. Genome-wide analysis captures the determinants of the antibiotic cross-resistance interaction network. Nat. Commun. 5, 4352 (2014).","journal-title":"Nat. Commun."},{"key":"1857_CR19","doi-asserted-by":"publisher","first-page":"2387","DOI":"10.1093\/molbev\/msu191","volume":"31","author":"T Oz","year":"2014","unstructured":"Oz, T. et al. Strength of selection pressure is an important parameter contributing to the complexity of antibiotic resistance evolution. Mol. Biol. Evol. 31, 2387\u20132401 (2014).","journal-title":"Mol. Biol. Evol."},{"key":"1857_CR20","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1099\/0022-1317-49-1-103","volume":"49","author":"M-A Arcangioli","year":"2000","unstructured":"Arcangioli, M.-A., Leroy-Setrin, S., Martel, J.-L. & Chaslus-Dancla, E. Evolution of chloramphenicol resistance, with emergence of cross-resistance to florfenicol, in bovine Salmonella Typhimurium strains implicates definitive phage type (DT) 104. J. Med. Microbiol. 49, 103\u2013110 (2000).","journal-title":"J. Med. Microbiol."},{"key":"1857_CR21","doi-asserted-by":"publisher","first-page":"1175","DOI":"10.1093\/molbev\/msv006","volume":"32","author":"M Rodriguez de Evgrafov","year":"2015","unstructured":"Rodriguez de Evgrafov, M., Gumpert, H., Munck, C., Thomsen, T. T. & Sommer, M. O. A. Collateral resistance and sensitivity modulate evolution of high-level resistance to drug combination treatment in Staphylococcus aureus. Mol. Biol. Evol. 32, 1175\u20131185 (2015).","journal-title":"Mol. Biol. Evol."},{"key":"1857_CR22","doi-asserted-by":"publisher","first-page":"2229","DOI":"10.1093\/molbev\/msx158","volume":"34","author":"C Barbosa","year":"2017","unstructured":"Barbosa, C. et al. Alternative evolutionary paths to bacterial antibiotic resistance cause distinct collateral effects. Mol. Biol. Evol. 34, 2229\u20132244 (2017).","journal-title":"Mol. Biol. Evol."},{"key":"1857_CR23","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1016\/j.cell.2017.12.012","volume":"172","author":"L Imamovic","year":"2018","unstructured":"Imamovic, L. et al. Drug-driven phenotypic convergence supports rational treatment strategies of chronic infections. Cell 172, 121\u2013134 (2018).","journal-title":"Cell"},{"key":"1857_CR24","doi-asserted-by":"publisher","first-page":"613","DOI":"10.1111\/1751-7915.13817","volume":"15","author":"P Laborda","year":"2022","unstructured":"Laborda, P., Mart\u00ednez, J. L. & Hernando-Amado, S. Convergent phenotypic evolution towards fosfomycin collateral sensitivity of Pseudomonas aeruginosa antibiotic-resistant mutants. Microb. Biotechnol. 15, 613\u2013629 (2022).","journal-title":"Microb. Biotechnol."},{"key":"1857_CR25","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2109370119","volume":"119","author":"S Hernando-Amado","year":"2022","unstructured":"Hernando-Amado, S., Laborda, P., Valverde, J. R. & Mart\u00ednez, J. L. Mutational background influences P. aeruginosa ciprofloxacin resistance evolution but preserves collateral sensitivity robustness. Proc. Natl Acad. Sci. USA 119, e2109370119 (2022).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"1857_CR26","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-37624-4","volume":"14","author":"DY Liu","year":"2023","unstructured":"Liu, D. Y. et al. Collateral sensitivity profiling in drug-resistant Escherichia coli identifies natural products suppressing cephalosporin resistance. Nat. Commun. 14, 1976 (2023).","journal-title":"Nat. Commun."},{"key":"1857_CR27","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms6792","volume":"5","author":"S Suzuki","year":"2014","unstructured":"Suzuki, S., Horinouchi, T. & Furusawa, C. Prediction of antibiotic resistance by gene expression profiles. Nat. Commun. 5, 5792 (2014).","journal-title":"Nat. Commun."},{"key":"1857_CR28","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-14335-7","volume":"7","author":"T Horinouchi","year":"2017","unstructured":"Horinouchi, T. et al. Prediction of cross-resistance and collateral sensitivity by gene expression profiles and genomic mutations. Sci. Rep. 7, 14009 (2017).","journal-title":"Sci. Rep."},{"key":"1857_CR29","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1016\/j.mib.2013.01.008","volume":"16","author":"AR Brochado","year":"2013","unstructured":"Brochado, A. R. & Typas, A. High-throughput approaches to understanding gene function and mapping network architecture in bacteria. Curr. Opin. Microbiol. 16, 199\u2013206 (2013).","journal-title":"Curr. Opin. Microbiol."},{"key":"1857_CR30","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1016\/j.coisb.2017.05.020","volume":"4","author":"E Cacace","year":"2017","unstructured":"Cacace, E., Kritikos, G. & Typas, A. Chemical genetics in drug discovery. Curr. Opin. Syst. Biol. 4, 35\u201342 (2017).","journal-title":"Curr. Opin. Syst. Biol."},{"key":"1857_CR31","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1016\/j.cell.2010.11.052","volume":"144","author":"RJ Nichols","year":"2011","unstructured":"Nichols, R. J. et al. Phenotypic landscape of a bacterial cell. Cell 144, 143\u2013156 (2011).","journal-title":"Cell"},{"key":"1857_CR32","doi-asserted-by":"publisher","first-page":"1583","DOI":"10.1126\/science.1238328","volume":"340","author":"B Ezraty","year":"2013","unstructured":"Ezraty, B. et al. Fe-S cluster biosynthesis controls uptake of aminoglycosides in a ROS-less death pathway. Science 340, 1583\u20131587 (2013).","journal-title":"Science"},{"key":"1857_CR33","doi-asserted-by":"publisher","first-page":"872","DOI":"10.15252\/msb.20156777","volume":"12","author":"S Chandrasekaran","year":"2016","unstructured":"Chandrasekaran, S. et al. Chemogenomics and orthology-based design of antibiotic combination therapies. Mol. Syst. Biol. 12, 872 (2016).","journal-title":"Mol. Syst. Biol."},{"key":"1857_CR34","doi-asserted-by":"publisher","first-page":"e1006124","DOI":"10.1371\/journal.pgen.1006124","volume":"12","author":"AL Shiver","year":"2016","unstructured":"Shiver, A. L. et al. A chemical\u2013genomic screen of neglected antibiotics reveals illicit transport of kasugamycin and blasticidin S. PLoS Genet. 12, e1006124 (2016).","journal-title":"PLoS Genet."},{"key":"1857_CR35","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1038\/s41586-018-0278-9","volume":"559","author":"AR Brochado","year":"2018","unstructured":"Brochado, A. R. et al. Species-specific activity of antibacterial drug combinations. Nature 559, 259\u2013263 (2018).","journal-title":"Nature"},{"key":"1857_CR36","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.02561-21","volume":"12","author":"MR Silvis","year":"2021","unstructured":"Silvis, M. R. et al. Morphological and transcriptional responses to CRISPRi knockdown of essential genes in Escherichia coli. mBio 12, e0256121 (2021).","journal-title":"mBio"},{"key":"1857_CR37","doi-asserted-by":"publisher","first-page":"5731","DOI":"10.1038\/s41467-019-13618-z","volume":"10","author":"B Kintses","year":"2019","unstructured":"Kintses, B. et al. Chemical-genetic profiling reveals limited cross-resistance between antimicrobial peptides with different modes of action. Nat. Commun. 10, 5731 (2019).","journal-title":"Nat. Commun."},{"key":"1857_CR38","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2006-7-7-r63","volume":"7","author":"SR Collins","year":"2006","unstructured":"Collins, S. R., Schuldiner, M., Krogan, N. J. & Weissman, J. S. A strategy for extracting and analyzing large-scale quantitative epistatic interaction data. Genome Biol. 7, R63 (2006).","journal-title":"Genome Biol."},{"key":"1857_CR39","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1016\/j.tim.2015.02.009","volume":"23","author":"C P\u00e1l","year":"2015","unstructured":"P\u00e1l, C., Papp, B. & L\u00e1z\u00e1r, V. Collateral sensitivity of antibiotic-resistant microbes. Trends Microbiol. 23, 401\u2013407 (2015).","journal-title":"Trends Microbiol."},{"key":"1857_CR40","doi-asserted-by":"publisher","first-page":"2142","DOI":"10.1128\/IAI.71.4.2142-2152.2003","volume":"71","author":"AK M\u00f8ller","year":"2003","unstructured":"M\u00f8ller, A. K. et al. An Escherichia coli MG1655 lipopolysaccharide deep-rough core mutant grows and survives in mouse cecal mucus but fails to colonize the mouse large intestine. Infect. Immun. 71, 2142\u20132152 (2003).","journal-title":"Infect. Immun."},{"key":"1857_CR41","doi-asserted-by":"publisher","first-page":"2537","DOI":"10.1016\/j.bpj.2015.10.013","volume":"109","author":"TM Nobre","year":"2015","unstructured":"Nobre, T. M. et al. Modification of Salmonella lipopolysaccharides prevents the outer membrane penetration of novobiocin. Biophys. J. 109, 2537\u20132545 (2015).","journal-title":"Biophys. J."},{"key":"1857_CR42","doi-asserted-by":"publisher","first-page":"473","DOI":"10.1038\/s41586-020-3002-5","volume":"588","author":"A Mateus","year":"2020","unstructured":"Mateus, A. et al. The functional proteome landscape of Escherichia coli. Nature 588, 473\u2013478 (2020).","journal-title":"Nature"},{"key":"1857_CR43","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1093\/jac\/32.2.195","volume":"32","author":"PG Mortimer","year":"1993","unstructured":"Mortimer, P. G. & Piddock, L. J. The accumulation of five antibacterial agents in porin-deficient mutants of Escherichia coli. J. Antimicrob. Chemother. 32, 195\u2013213 (1993).","journal-title":"J. Antimicrob. Chemother."},{"key":"1857_CR44","doi-asserted-by":"publisher","first-page":"4327","DOI":"10.1128\/AAC.49.10.4327-4334.2005","volume":"49","author":"M Hu","year":"2005","unstructured":"Hu, M., Nandi, S., Davies, C. & Nicholas, R. A. High-level chromosomally mediated tetracycline resistance in Neisseria gonorrhoeae results from a point mutation in the rpsJ gene encoding ribosomal protein S10 in combination with the mtrR and penB resistance determinants. Antimicrob. Agents Chemother. 49, 4327\u20134334 (2005).","journal-title":"Antimicrob. Agents Chemother."},{"key":"1857_CR45","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1128\/MMBR.66.4.671-701.2002","volume":"66","author":"S Grkovic","year":"2002","unstructured":"Grkovic, S., Brown, M. H. & Skurray, R. A. Regulation of bacterial drug export systems. Microbiol. Mol. Biol. Rev. 66, 671\u2013701 (2002).","journal-title":"Microbiol. Mol. Biol. Rev."},{"key":"1857_CR46","doi-asserted-by":"publisher","first-page":"647","DOI":"10.1002\/pro.3769","volume":"29","author":"GA Beggs","year":"2020","unstructured":"Beggs, G. A., Brennan, R. G. & Arshad, M. MarR family proteins are important regulators of clinically relevant antibiotic resistance. Protein Sci. 29, 647\u2013653 (2020).","journal-title":"Protein Sci."},{"key":"1857_CR47","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1038\/s41586-018-0124-0","volume":"557","author":"MN Price","year":"2018","unstructured":"Price, M. N. et al. Mutant phenotypes for thousands of bacterial genes of unknown function. Nature 557, 503\u2013509 (2018).","journal-title":"Nature"},{"key":"1857_CR48","doi-asserted-by":"publisher","first-page":"1318","DOI":"10.1128\/AAC.33.8.1318","volume":"33","author":"SP Cohen","year":"1989","unstructured":"Cohen, S. P., McMurry, L. M., Hooper, D. C., Wolfson, J. S. & Levy, S. B. Cross-resistance to fluoroquinolones in multiple-antibiotic-resistant (Mar) Escherichia coli selected by tetracycline or chloramphenicol: decreased drug accumulation associated with membrane changes in addition to OmpF reduction. Antimicrob. Agents Chemother. 33, 1318\u20131325 (1989).","journal-title":"Antimicrob. Agents Chemother."},{"key":"1857_CR49","doi-asserted-by":"publisher","first-page":"998","DOI":"10.1128\/jb.177.4.998-1007.1995","volume":"177","author":"DG Thanassi","year":"1995","unstructured":"Thanassi, D. G., Suh, G. S. & Nikaido, H. Role of outer membrane barrier in efflux-mediated tetracycline resistance of Escherichia coli. J. Bacteriol. 177, 998\u20131007 (1995).","journal-title":"J. Bacteriol."},{"key":"1857_CR50","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1128\/MMBR.67.4.593-656.2003","volume":"67","author":"H Nikaido","year":"2003","unstructured":"Nikaido, H. Molecular basis of bacterial outer membrane permeability revisited. Microbiol. Mol. Biol. Rev. 67, 593\u2013656 (2003).","journal-title":"Microbiol. Mol. Biol. Rev."},{"key":"1857_CR51","doi-asserted-by":"publisher","first-page":"e2001586","DOI":"10.1371\/journal.pbio.2001586","volume":"15","author":"P Yen","year":"2017","unstructured":"Yen, P. & Papin, J. A. History of antibiotic adaptation influences microbial evolutionary dynamics during subsequent treatment. PLoS Biol. 15, e2001586 (2017).","journal-title":"PLoS Biol."},{"key":"1857_CR52","doi-asserted-by":"publisher","first-page":"3673","DOI":"10.1038\/s41467-018-06143-y","volume":"9","author":"NL Podnecky","year":"2018","unstructured":"Podnecky, N. L. et al. Conserved collateral antibiotic susceptibility networks in diverse clinical strains of Escherichia coli. Nat. Commun. 9, 3673 (2018).","journal-title":"Nat. Commun."},{"key":"1857_CR53","doi-asserted-by":"publisher","first-page":"1493","DOI":"10.1016\/j.cell.2016.05.003","volume":"165","author":"JM Peters","year":"2016","unstructured":"Peters, J. M. et al. A comprehensive, CRISPR-based functional analysis of essential genes in bacteria. Cell 165, 1493\u20131506 (2016).","journal-title":"Cell"},{"key":"1857_CR54","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1038\/s41586-019-1315-z","volume":"571","author":"EO Johnson","year":"2019","unstructured":"Johnson, E. O. et al. Large-scale chemical\u2013genetics yields new M. tuberculosis inhibitor classes. Nature 571, 72\u201378 (2019).","journal-title":"Nature"},{"key":"1857_CR55","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.108789","volume":"34","author":"H Liu","year":"2021","unstructured":"Liu, H. et al. Functional genetics of human gut commensal Bacteroides thetaiotaomicron reveals metabolic requirements for growth across environments. Cell Rep. 34, 108789 (2021).","journal-title":"Cell Rep."},{"key":"1857_CR56","doi-asserted-by":"publisher","unstructured":"Shiver, A. L. et al. A mutant fitness compendium in bifidobacteria reveals molecular determinants of colonization and host\u2013microbe interactions. Preprint at bioRxiv https:\/\/doi.org\/10.1101\/2023.08.29.555234 (2023).","DOI":"10.1101\/2023.08.29.555234"},{"key":"1857_CR57","doi-asserted-by":"publisher","first-page":"1580","DOI":"10.1038\/s41564-022-01208-7","volume":"7","author":"F Rosconi","year":"2022","unstructured":"Rosconi, F. et al. A bacterial pan-genome makes gene essentiality strain-dependent and evolvable. Nat. Microbiol. 7, 1580\u20131592 (2022).","journal-title":"Nat. Microbiol."},{"key":"1857_CR58","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1038\/s41564-020-00839-y","volume":"6","author":"F Rousset","year":"2021","unstructured":"Rousset, F. et al. The impact of genetic diversity on gene essentiality within the Escherichia coli species. Nat. Microbiol. 6, 301\u2013312 (2021).","journal-title":"Nat. Microbiol."},{"key":"1857_CR59","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2023.113519","volume":"43","author":"CGP Voogdt","year":"2023","unstructured":"Voogdt, C. G. P. et al. Randomly barcoded transposon mutant libraries for gut commensals II: applying libraries for functional genetics. Cell Rep. 43, 113519 (2023).","journal-title":"Cell Rep."},{"key":"1857_CR60","doi-asserted-by":"publisher","DOI":"10.1038\/msb4100050","volume":"2","author":"T Baba","year":"2006","unstructured":"Baba, T. et al. Construction of Escherichia coli K-12 in-frame, single-gene knockout mutants: the Keio collection. Mol. Syst. Biol. 2, 2006.0008 (2006).","journal-title":"Mol. Syst. Biol."},{"key":"1857_CR61","doi-asserted-by":"publisher","first-page":"e99820","DOI":"10.1371\/journal.pone.0099820","volume":"9","author":"S Porwollik","year":"2014","unstructured":"Porwollik, S. et al. Defined single-gene and multi-gene deletion mutant collections in Salmonella enterica sv Typhimurium. PLoS ONE 9, e99820 (2014).","journal-title":"PLoS ONE"},{"key":"1857_CR62","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1016\/j.cels.2016.12.013","volume":"4","author":"B-M Koo","year":"2017","unstructured":"Koo, B.-M. et al. Construction and analysis of two genome-scale deletion libraries for Bacillus subtilis. Cell Syst. 4, 291\u2013305 (2017).","journal-title":"Cell Syst."},{"key":"1857_CR63","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2023.113517","volume":"43","author":"S Tripathi","year":"2023","unstructured":"Tripathi, S. et al. Randomly barcoded transposon mutant libraries for gut commensals I: strategies for efficient library construction. Cell Rep. 43, 113517 (2023).","journal-title":"Cell Rep."},{"key":"1857_CR64","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1038\/s41596-021-00639-6","volume":"17","author":"V de Bakker","year":"2022","unstructured":"de Bakker, V., Liu, X., Bravo, A. M. & Veening, J.-W. CRISPRi-seq for genome-wide fitness quantification in bacteria. Nat. Protoc. 17, 252\u2013281 (2022).","journal-title":"Nat. Protoc."},{"key":"1857_CR65","doi-asserted-by":"publisher","DOI":"10.1126\/science.abf8424","volume":"372","author":"M Costanzo","year":"2021","unstructured":"Costanzo, M. et al. Environmental robustness of the global yeast genetic interaction network. Science 372, eabf8424 (2021).","journal-title":"Science"},{"key":"1857_CR66","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.68876","volume":"10","author":"A Batra","year":"2021","unstructured":"Batra, A. et al. High potency of sequential therapy with only \u03b2-lactam antibiotics. eLife 10, e68876 (2021).","journal-title":"eLife"},{"key":"1857_CR67","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-08529-y","volume":"10","author":"CEH Rosenkilde","year":"2019","unstructured":"Rosenkilde, C. E. H. et al. Collateral sensitivity constrains resistance evolution of the CTX-M-15 \u03b2-lactamase. Nat. Commun. 10, 618 (2019).","journal-title":"Nat. Commun."},{"key":"1857_CR68","doi-asserted-by":"publisher","first-page":"334","DOI":"10.1038\/s41467-018-08098-6","volume":"10","author":"D Nichol","year":"2019","unstructured":"Nichol, D. et al. Antibiotic collateral sensitivity is contingent on the repeatability of evolution. Nat. Commun. 10, 334 (2019).","journal-title":"Nat. Commun."},{"key":"1857_CR69","doi-asserted-by":"publisher","first-page":"1601","DOI":"10.1093\/molbev\/msz109","volume":"36","author":"G Apjok","year":"2019","unstructured":"Apjok, G. et al. Limited evolutionary conservation of the phenotypic effects of antibiotic resistance mutations. Mol. Biol. Evol. 36, 1601\u20131611 (2019).","journal-title":"Mol. Biol. Evol."},{"key":"1857_CR70","doi-asserted-by":"publisher","first-page":"862","DOI":"10.1016\/j.tim.2016.06.009","volume":"24","author":"GD Wright","year":"2016","unstructured":"Wright, G. D. Antibiotic adjuvants: rescuing antibiotics from resistance. Trends Microbiol. 24, 862\u2013871 (2016).","journal-title":"Trends Microbiol."},{"key":"1857_CR71","doi-asserted-by":"publisher","first-page":"623","DOI":"10.1038\/nature25979","volume":"555","author":"L Maier","year":"2018","unstructured":"Maier, L. et al. Extensive impact of non-antibiotic drugs on human gut bacteria. Nature 555, 623\u2013628 (2018).","journal-title":"Nature"},{"key":"1857_CR72","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1038\/s41579-018-0141-x","volume":"17","author":"M Tyers","year":"2019","unstructured":"Tyers, M. & Wright, G. D. Drug combinations: a strategy to extend the life of antibiotics in the 21st century. Nat. Rev. Microbiol. 17, 141\u2013155 (2019).","journal-title":"Nat. Rev. Microbiol."},{"key":"1857_CR73","doi-asserted-by":"publisher","first-page":"e0105521","DOI":"10.1128\/mSystems.01055-21","volume":"6","author":"RC Allen","year":"2021","unstructured":"Allen, R. C., Pfrunder-Cardozo, K. R. & Hall, A. R. Collateral sensitivity interactions between antibiotics depend on local abiotic conditions. mSystems 6, e0105521 (2021).","journal-title":"mSystems"},{"key":"1857_CR74","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.47612","volume":"8","author":"A Santos-Lopez","year":"2019","unstructured":"Santos-Lopez, A., Marshall, C. W., Scribner, M. R., Snyder, D. J. & Cooper, V. S. Evolutionary pathways to antibiotic resistance are dependent upon environmental structure and bacterial lifestyle. eLife 8, e47612 (2019).","journal-title":"eLife"},{"key":"1857_CR75","doi-asserted-by":"publisher","first-page":"1479","DOI":"10.1126\/science.287.5457.1479","volume":"287","author":"J Bj\u00f6rkman","year":"2000","unstructured":"Bj\u00f6rkman, J., Nagaev, I., Berg, O. G., Hughes, D. & Andersson, D. I. Effects of environment on compensatory mutations to ameliorate costs of antibiotic resistance. Science 287, 1479\u20131482 (2000).","journal-title":"Science"},{"key":"1857_CR76","doi-asserted-by":"publisher","first-page":"2196","DOI":"10.1038\/s41564-023-01486-9","volume":"8","author":"E Cacace","year":"2023","unstructured":"Cacace, E. et al. Systematic analysis of drug combinations against Gram-positive bacteria. Nat. Microbiol. 8, 2196\u20132212 (2023).","journal-title":"Nat. Microbiol."},{"key":"1857_CR77","doi-asserted-by":"publisher","first-page":"540","DOI":"10.1038\/s41586-022-05260-5","volume":"610","author":"V L\u00e1z\u00e1r","year":"2022","unstructured":"L\u00e1z\u00e1r, V., Snitser, O., Barkan, D. & Kishony, R. Antibiotic combinations reduce Staphylococcus aureus clearance. Nature 610, 540\u2013546 (2022).","journal-title":"Nature"},{"key":"1857_CR78","doi-asserted-by":"publisher","first-page":"17014","DOI":"10.1038\/nmicrobiol.2017.14","volume":"2","author":"G Kritikos","year":"2017","unstructured":"Kritikos, G. et al. A tool named Iris for versatile high-throughput phenotyping in microorganisms. Nat. Microbiol. 2, 17014 (2017).","journal-title":"Nat. Microbiol."},{"key":"1857_CR79","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1038\/s41592-019-0686-2","volume":"17","author":"P Virtanen","year":"2020","unstructured":"Virtanen, P. et al. SciPy 1.0: fundamental algorithms for scientific computing in Python. Nat. Methods 17, 261\u2013272 (2020).","journal-title":"Nat. Methods"},{"key":"1857_CR80","doi-asserted-by":"crossref","unstructured":"Breiman, L., Friedman, J., Olshen, R. A. & Stone, C. J. Classification and Regression Trees (Routledge, 2017).","DOI":"10.1201\/9781315139470"},{"key":"1857_CR81","first-page":"2825","volume":"12","author":"F Pedregosa","year":"2011","unstructured":"Pedregosa, F. et al. Scikit-learn: machine learning in Python. J. Mach. Learn. Res. 12, 2825\u20132830 (2011).","journal-title":"J. Mach. Learn. Res."},{"key":"1857_CR82","doi-asserted-by":"publisher","first-page":"e0146021","DOI":"10.1371\/journal.pone.0146021","volume":"10","author":"C Ritz","year":"2015","unstructured":"Ritz, C., Baty, F., Streibig, J. C. & Gerhard, D. Dose\u2013response analysis using R. PLoS ONE 10, e0146021 (2015).","journal-title":"PLoS ONE"},{"key":"1857_CR83","doi-asserted-by":"publisher","first-page":"D20","DOI":"10.1093\/nar\/gkab1112","volume":"50","author":"EW Sayers","year":"2021","unstructured":"Sayers, E. W. et al. Database resources of the National Center for Biotechnology Information. Nucleic Acids Res. 50, D20\u2013D26 (2021).","journal-title":"Nucleic Acids Res."},{"key":"1857_CR84","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1007\/978-1-4939-0554-6_12","volume":"1151","author":"DE Deatherage","year":"2014","unstructured":"Deatherage, D. E. & Barrick, J. E. Identification of mutations in laboratory evolved microbes from next-generation sequencing data using breseq. Methods Mol. Biol. 1151, 165\u2013188 (2014).","journal-title":"Methods Mol. Biol."},{"key":"1857_CR85","doi-asserted-by":"publisher","first-page":"1.17.1","DOI":"10.1002\/0471142727.mb0117s79","volume":"79","author":"LC Thomason","year":"2007","unstructured":"Thomason, L. C., Costantino, N. & Court, D. L. E. coli genome manipulation by P1 transduction. Curr. Protoc. Mol. Biol. 79, 1.17.1\u20131.17.8 (2007).","journal-title":"Curr. Protoc. Mol. Biol."},{"key":"1857_CR86","doi-asserted-by":"publisher","unstructured":"Sakenova, N. et al. Systematic mapping of antibiotic cross-resistance and collateral sensitivity with chemical genetics. Zenodo https:\/\/doi.org\/10.5281\/zenodo.10572857 (2024).","DOI":"10.5281\/zenodo.10572857"}],"container-title":["Nature Microbiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41564-024-01857-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41564-024-01857-w","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41564-024-01857-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,5]],"date-time":"2025-02-05T10:27:48Z","timestamp":1738751268000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41564-024-01857-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,2]]},"references-count":86,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,1]]}},"alternative-id":["1857"],"URL":"https:\/\/doi.org\/10.1038\/s41564-024-01857-w","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2024.01.25.576750","asserted-by":"object"}]},"ISSN":["2058-5276"],"issn-type":[{"value":"2058-5276","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,2]]},"assertion":[{"value":"24 January 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 October 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 December 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}