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Understanding the causes of this cost is of paramount importance, as it is one of the main determinants of the prevalence of resistances upon reducing antibiotics use. Here we show that the fitness costs of antibiotic resistance mutations that affect transcription and translation in Escherichia coli strongly correlate with DNA breaks, which are generated via transcription\u2013translation uncoupling, increased formation of RNA\u2013DNA hybrids (R-loops), and elevated replication\u2013transcription conflicts. We also demonstrated that the mechanisms generating DNA breaks are repeatedly targeted by compensatory evolution, and that DNA breaks and the cost of resistance can be increased by targeting the RNase HI, which specifically degrades R-loops. We further show that the DNA damage and thus the fitness cost caused by lack of RNase HI function drive resistant clones to extinction in populations with high initial frequency of resistance, both in laboratory conditions and in a mouse model of gut colonization. Thus, RNase HI provides a target specific against resistant bacteria, which we validate using a repurposed drug. In summary, we revealed key mechanisms underlying the fitness cost of antibiotic resistance mutations that can be exploited to specifically eliminate resistant bacteria.<\/jats:p>","DOI":"10.1093\/molbev\/msab093","type":"journal-article","created":{"date-parts":[[2021,4,7]],"date-time":"2021-04-07T15:10:24Z","timestamp":1617808224000},"page":"3220-3234","source":"Crossref","is-referenced-by-count":16,"title":["DNA Breaks-Mediated Fitness Cost Reveals RNase HI as a New Target for Selectively Eliminating Antibiotic-Resistant Bacteria"],"prefix":"10.1093","volume":"38","author":[{"given":"Roberto","family":"Balbont\u00edn","sequence":"first","affiliation":[{"name":"Instituto Gulbenkian de Ci\u00eancia, Oeiras, Portugal"}]},{"given":"Nelson","family":"Fraz\u00e3o","sequence":"additional","affiliation":[{"name":"Instituto Gulbenkian de Ci\u00eancia, Oeiras, Portugal"}]},{"given":"Isabel","family":"Gordo","sequence":"additional","affiliation":[{"name":"Instituto Gulbenkian de Ci\u00eancia, Oeiras, Portugal"}]}],"member":"286","published-online":{"date-parts":[[2021,4,8]]},"reference":[{"issue":"7","key":"2021072920002144900_msab093-B1","doi-asserted-by":"crossref","first-page":"1417","DOI":"10.1093\/jac\/dkr173","article-title":"Molecular basis and mechanisms of drug resistance in Mycobacterium tuberculosis: classical and new drugs","volume":"66","author":"Almeida Da Silva","year":"2011","journal-title":"J Antimicrob Chemother"},{"issue":"2","key":"2021072920002144900_msab093-B2","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1093\/femsre\/fuaa001","article-title":"Antibiotic resistance: turning evolutionary principles into clinical reality","volume":"44","author":"Andersson","year":"2020","journal-title":"FEMS Microbiol Rev"},{"issue":"4","key":"2021072920002144900_msab093-B3","doi-asserted-by":"crossref","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"},{"issue":"5","key":"2021072920002144900_msab093-B4","doi-asserted-by":"crossref","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"},{"issue":"14","key":"2021072920002144900_msab093-B5","doi-asserted-by":"crossref","first-page":"5087","DOI":"10.1128\/JB.01976-07","article-title":"Impact of individual mutations on increased fitness in adaptively evolved strains of Escherichia coli","volume":"190","author":"Applebee","year":"2008","journal-title":"J Bacteriol"},{"issue":"6","key":"2021072920002144900_msab093-B6","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1111\/1751-7915.12182","article-title":"Mutualistic interaction between Salmonella enterica and Aspergillus niger and its effects on Zea mays colonization","volume":"7","author":"Balbont\u00edn","year":"2014","journal-title":"Microb Biotechnol"},{"issue":"8","key":"2021072920002144900_msab093-B7","doi-asserted-by":"crossref","first-page":"3649","DOI":"10.1128\/AAC.00013-11","article-title":"Ecology and evolution as targets: the need for novel eco-evo drugs and strategies to fight antibiotic resistance","volume":"55","author":"Baquero","year":"2011","journal-title":"Antimicrob Agents Chemother"},{"issue":"3","key":"2021072920002144900_msab093-B8","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1128\/jb.62.3.293-300.1951","article-title":"Studies on lysogenesis. 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