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Resistance to antimicrobial peptides (AMPs) is a key feature of urogenital pathogenesis of the closely related species, <jats:italic>Neisseria gonorrhoeae<\/jats:italic>. The US_NmUC isolates were found to be highly resistant to the model AMP, polymyxin B (PmB, MICs 64\u2013256\u00a0\u00b5g\u00a0ml<jats:sup>\u20131<\/jats:sup>). The isolates also demonstrated stable subpopulations of heteroresistant colonies that showed near total resistant to PmB (MICs 384\u20131024\u00a0\u00b5g\u00a0ml<jats:sup>\u20131<\/jats:sup>) and colistin (MIC 256\u00a0\u00b5g\u00a0ml<jats:sup>\u20131<\/jats:sup>) as well as enhanced LL\u201037 resistance. This is the first observation of heteroresistance in <jats:italic>N. meningitidis<\/jats:italic>. Consistent with previous findings, overall PmB resistance in US_NmUC isolates was due to active Mtr efflux and LptA\u2010mediated lipid A modification. However, whole genome sequencing, variant analyses and directed mutagenesis revealed that the heteroresistance phenotypes and very high\u2010level AMP resistance were the result of point mutations and IS1655 element movement in the <jats:italic>pilMNOPQ<\/jats:italic> operon, encoding the type IV pilin biogenesis apparatus. Cross\u2010resistance to other classes of antibiotics was also observed in the heteroresistant colonies. High\u2010level resistance to AMPs may contribute to the pathogenesis of US_NmUC.<\/jats:p>","DOI":"10.1111\/mmi.14153","type":"journal-article","created":{"date-parts":[[2018,10,19]],"date-time":"2018-10-19T06:13:51Z","timestamp":1539929631000},"page":"254-268","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Heteroresistance to the model antimicrobial peptide polymyxin B in the emerging <i>Neisseria meningitidis<\/i> lineage 11.2 urethritis clade: mutations in the <i>pilMNOPQ<\/i> operon"],"prefix":"10.1111","volume":"111","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7950-8197","authenticated-orcid":false,"given":"Yih\u2010Ling","family":"Tzeng","sequence":"first","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine Emory University School of Medicine Atlanta GA 30322 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