title: Colistin resistance in Acinetobacter baumannii is mediated by complete loss of lipopolysaccharide production.
abstract: Infections caused by multidrug-resistant (MDR) Gram-negative bacteria represent a major global health problem. Polymyxin antibiotics such as colistin have resurfaced as effective last-resort antimicrobials for use against MDR Gram-negative pathogens, including Acinetobacter baumannii. Here we show that A. baumannii can rapidly develop resistance to polymyxin antibiotics by complete loss of the initial binding target, the lipid A component of lipopolysaccharide (LPS), which has long been considered to be essential for the viability of Gram-negative bacteria. We characterized 13 independent colistin-resistant derivatives of A. baumannii type strain ATCC 19606 and showed that all contained mutations within one of the first three genes of the lipid A biosynthesis pathway: lpxA, lpxC, and lpxD. All of these mutations resulted in the complete loss of LPS production. Furthermore, we showed that loss of LPS occurs in a colistin-resistant clinical isolate of A. baumannii. This is the first report of a spontaneously occurring, lipopolysaccharide-deficient, Gram-negative bacterium.
authors.affiliation: Department of Microbiology, Building 76, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Moffatt
authors.forename: Marina
authors.initials: M
authors.lastname: Harper
authors.forename: Paul
authors.initials: P
authors.lastname: Harrison
authors.forename: John D F
authors.initials: JD
authors.lastname: Hale
authors.forename: Evgeny
authors.initials: E
authors.lastname: Vinogradov
authors.forename: Torsten
authors.initials: T
authors.lastname: Seemann
authors.forename: Rebekah
authors.initials: R
authors.lastname: Henry
authors.forename: Bethany
authors.initials: B
authors.lastname: Crane
authors.forename: Frank
authors.initials: F
authors.lastname: St Michael
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Cox
authors.forename: Ben
authors.initials: B
authors.lastname: Adler
authors.forename: Roger L
authors.initials: RL
authors.lastname: Nation
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.forename: John D
authors.initials: JD
authors.lastname: Boyce
mesh_terms: D040981:Acinetobacter baumannii / Q000187:drug effects* / Q000378:metabolism*; D000217:Acyltransferases / Q000235:genetics; D000581:Amidohydrolases / Q000235:genetics; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics; D003091:Colistin / Q000494:pharmacology*; D024901:Drug Resistance, Multiple, Bacterial / Q000235:genetics; D005816:Genetic Complementation Test; D008070:Lipopolysaccharides / Q000378:metabolism*; D046529:Microscopy, Electron, Transmission; D009154:Mutation
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D008070:Lipopolysaccharides; D000217:Acyltransferases; D000581:Amidohydrolases; D003091:Colistin