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We hypothesized that antimicrobial resistance can be reversed by targeting chromosomal non-essential genes that are not responsible for acquired resistance but essential for resistant bacteria under therapeutic concentrations of antimicrobials. Conditional essentiality of individual genes to antimicrobial resistance was evaluated in an epidemic multidrug-resistant clone of <jats:italic>K. pneumoniae<\/jats:italic> (ST258). We constructed a high-density transposon mutant library of &gt;430,000 unique Tn<jats:italic>5<\/jats:italic> insertions and measured mutant depletion upon exposure to three clinically relevant antimicrobials (colistin, imipenem or ciprofloxacin) by <jats:underline>Tra<\/jats:underline>nsposon <jats:underline>D<\/jats:underline>irected <jats:underline>I<\/jats:underline>nsertion-site <jats:underline>S<\/jats:underline>equencing (TraDIS). Using this high-throughput approach, we defined three sets of chromosomal non-essential genes essential for growth during exposure to colistin (n\u2009=\u200935), imipenem (n\u2009=\u20091) or ciprofloxacin (n\u2009=\u20091) in addition to known resistance determinants, collectively termed the \u201csecondary resistome\u201d. As proof of principle, we demonstrated that inactivation of a non-essential gene not previously found linked to colistin resistance (<jats:italic>dedA<\/jats:italic>) restored colistin susceptibility by reducing the minimum inhibitory concentration from 8 to 0.5\u2009\u03bcg\/ml, 4-fold below the susceptibility breakpoint (S\u2009\u2264\u20092\u2009\u03bcg\/ml). This finding suggests that the secondary resistome is a potential target for developing antimicrobial \u201chelper\u201d drugs that restore the efficacy of existing antimicrobials.<\/jats:p>","DOI":"10.1038\/srep42483","type":"journal-article","created":{"date-parts":[[2017,2,15]],"date-time":"2017-02-15T10:10:50Z","timestamp":1487153450000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":90,"title":["The secondary resistome of multidrug-resistant Klebsiella pneumoniae"],"prefix":"10.1038","volume":"7","author":[{"given":"Bimal","family":"Jana","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy K.","family":"Cain","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William T.","family":"Doerrler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine J.","family":"Boinett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria C.","family":"Fookes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julian","family":"Parkhill","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Guardabassi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,2,15]]},"reference":[{"key":"BFsrep42483_CR1","unstructured":"Jim, O\u2019Neill. 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