title: Biological cost of different mechanisms of colistin resistance and their impact on virulence in Acinetobacter baumannii.
abstract: Two mechanisms of resistance to colistin have been described in Acinetobacter baumannii. One involves complete loss of lipopolysaccharide (LPS), resulting from mutations in lpxA, lpxC, or lpxD, and the second is associated with phosphoethanolamine addition to LPS, mediated through mutations in pmrAB. In order to assess the clinical impacts of both resistance mechanisms, A. baumannii ATCC 19606 and its isogenic derivatives, AL1851 ΔlpxA, AL1852 ΔlpxD, AL1842 ΔlpxC, and ATCC 19606 pmrB, were analyzed for in vitro growth rate, in vitro and in vivo competitive growth, infection of A549 respiratory alveolar epithelial cells, virulence in the Caenorhabditis elegans model, and virulence in a systemic mouse infection model. The in vitro growth rate of the lpx mutants was clearly diminished; furthermore, in vitro and in vivo competitive-growth experiments revealed a reduction in fitness for both mutant types. Infection of A549 cells with ATCC 19606 or the pmrB mutant resulted in greater loss of viability than with lpx mutants. Finally, the lpx mutants were highly attenuated in both the C. elegans and mouse infection models, while the pmrB mutant was attenuated only in the C. elegans model. In summary, while colistin resistance in A. baumannii confers a clear selective advantage in the presence of colistin treatment, it causes a noticeable cost in terms of overall fitness and virulence, with a more striking reduction associated with LPS loss than with phosphoethanolamine addition. Therefore, we hypothesize that colistin resistance mediated by changes in pmrAB will be more likely to arise in clinical settings in patients treated with colistin.
authors.affiliation: Servicio de Microbiología-INIBIC, Complejo Hospitalario Universitario A Coruña (CHUAC), A Coruña, Spain.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Beceiro
authors.forename: Antonio
authors.initials: A
authors.lastname: Moreno
authors.forename: Nathalie
authors.initials: N
authors.lastname: Fernández
authors.forename: Juán A
authors.initials: JA
authors.lastname: Vallejo
authors.forename: Jesús
authors.initials: J
authors.lastname: Aranda
authors.forename: Ben
authors.initials: B
authors.lastname: Adler
authors.forename: Marina
authors.initials: M
authors.lastname: Harper
authors.forename: John D
authors.initials: JD
authors.lastname: Boyce
authors.forename: Germán
authors.initials: G
authors.lastname: Bou
mesh_terms: D040981:Acinetobacter baumannii / Q000187:drug effects* / Q000472:pathogenicity*; D000818:Animals; D002460:Cell Line; D003091:Colistin / Q000494:pharmacology* / Q000627:therapeutic use*; D024881:Drug Resistance, Bacterial; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D014774:Virulence
chemical_list: D003091:Colistin