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These inhibitors compete with the beta-lactam antibiotic for the same binding site on the beta-lactamase, thus generating an evolutionary tradeoff: mutations that increase the enzyme\u2019s beta-lactamase activity tend to increase also its susceptibility to the inhibitor. Here, we investigate how common and accessible are mutants that escape this adaptive tradeoff. Screening a deep mutant library of the\n                    <jats:italic>bla<\/jats:italic>\n                    <jats:sub>\n                      <jats:italic>ampC<\/jats:italic>\n                    <\/jats:sub>\n                    beta-lactamase gene of\n                    <jats:italic>Escherichia coli<\/jats:italic>\n                    , we identified mutations that allow growth at beta-lactam concentrations far exceeding those inhibiting growth of the wildtype strain, even in the presence of the enzyme inhibitor (avibactam). These escape mutations are rare and drug-specific, and some combinations of avibactam with beta-lactam drugs appear to prevent such escape phenotypes. Our results, showing differential adaptive potential of\n                    <jats:italic>bla<\/jats:italic>\n                    <jats:sub>\n                      <jats:italic>ampC<\/jats:italic>\n                    <\/jats:sub>\n                    to combinations of avibactam and different beta-lactam antibiotics, suggest that it may be possible to identify treatments that are more resilient to evolution of resistance.\n                  <\/jats:p>","DOI":"10.1038\/s41467-020-15666-2","type":"journal-article","created":{"date-parts":[[2020,4,24]],"date-time":"2020-04-24T06:27:15Z","timestamp":1587709635000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["Escape mutations circumvent a tradeoff between resistance to a beta-lactam and resistance to a beta-lactamase inhibitor"],"prefix":"10.1038","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4372-7958","authenticated-orcid":false,"given":"Dor","family":"Russ","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabian","family":"Glaser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Einat","family":"Shaer Tamar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2515-4113","authenticated-orcid":false,"given":"Idan","family":"Yelin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1303-5598","authenticated-orcid":false,"given":"Michael","family":"Baym","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5331-5204","authenticated-orcid":false,"given":"Eric D.","family":"Kelsic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Zampaloni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Haldimann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5013-5072","authenticated-orcid":false,"given":"Roy","family":"Kishony","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,4,24]]},"reference":[{"key":"15666_CR1","doi-asserted-by":"publisher","first-page":"742","DOI":"10.1016\/S1473-3099(14)70780-7","volume":"14","author":"TP Van Boeckel","year":"2014","unstructured":"Van Boeckel, T. 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