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ECC are increasingly isolated from healthcare\u2010associated infections, demonstrating that these Enterobacteriaceae are emerging nosocomial pathogens. ECC can rapidly acquire multidrug resistance to conventional antibiotics. Cationic antimicrobial peptides (CAMPs) have served as therapeutic alternatives because they target the highly conserved lipid A component of the Gram\u2010negative outer membrane. Many Enterobacteriaceae fortify their outer membrane with cationic amine\u2010containing moieties to prevent CAMP binding, which can lead to cell lysis. The PmrAB two\u2010component system (TCS) directly activates 4\u2010amino\u20104\u2010deoxy\u2010<jats:sc>l<\/jats:sc>\u2010arabinose (<jats:sc>l<\/jats:sc>\u2010Ara4N) biosynthesis to result in cationic amine moiety addition to lipid A in many Enterobacteriaceae such as <jats:italic>E. coli<\/jats:italic> and <jats:italic>Salmonella<\/jats:italic>. In contrast, PmrAB is dispensable for CAMP resistance in <jats:italic>E. cloacae<\/jats:italic>. Interestingly, some ECC clusters exhibit colistin heteroresistance, where a subpopulation of cells exhibit clinically significant resistance levels compared to the majority population. We demonstrate that <jats:italic>E. cloacae<\/jats:italic> lipid A is modified with <jats:sc>l<\/jats:sc>\u2010Ara4N to induce CAMP heteroresistance and the regulatory mechanism is independent of the PmrAB<jats:sub>Ecl<\/jats:sub> TCS. Instead, PhoP<jats:sub>Ecl <\/jats:sub>binds to the <jats:italic>arnB<jats:sub>Ecl<\/jats:sub><\/jats:italic> promoter to induce <jats:sc>l<\/jats:sc>\u2010Ara4N biosynthesis and PmrAB\u2010independent addition to the lipid A disaccharolipid. Therefore, PhoPQ<jats:sub>Ecl <\/jats:sub>contributes to regulation of CAMP heteroresistance in some ECC clusters.<\/jats:p>","DOI":"10.1111\/mmi.14240","type":"journal-article","created":{"date-parts":[[2019,3,15]],"date-time":"2019-03-15T08:13:18Z","timestamp":1552637598000},"page":"1604-1616","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":93,"title":["Colistin heteroresistance in <i>Enterobacter cloacae<\/i> is regulated by PhoPQ\u2010dependent 4\u2010amino\u20104\u2010deoxy\u2010<scp>l<\/scp>\u2010arabinose addition to lipid A"],"prefix":"10.1111","volume":"111","author":[{"given":"Katie N.","family":"Kang","sequence":"first","affiliation":[{"name":"Department of Biology University of Texas at Arlington Arlington TX USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dustin R.","family":"Klein","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Texas at Austin Austin TX 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