title: Loss of LPS is involved in the virulence and resistance to colistin of colistin-resistant Acinetobacter nosocomialis mutants selected in vitro.
abstract: OBJECTIVE
  Acinetobacter nosocomialis has increasingly been reported as an opportunistic pathogen causing nosocomial infections. Although it is more susceptible to all antimicrobial agents than Acinetobacter baumannii, MDR clinical isolates have also been described. In addition, several studies have shown a high percentage of resistance to colistin. Therefore, in the present study we investigated the mechanism of resistance to colistin in this microorganism.
  
  
  METHODS
  Colistin-resistant strains were selected from the original colistin-susceptible A. nosocomialis strain following multi-step mutant selection. Comparative genomic and proteomic analyses of both colistin-susceptible and colistin-resistant A. nosocomialis strains were performed. In addition, virulence was investigated using the Caenorhabditis elegans assay.
  
  
  RESULTS
  The colistin-resistant mutants selected showed a lower resistance profile for other types of antibacterial agents together with a significant decrease in virulence. The LT50 (i.e. time required to kill 50% of the nematodes) for the colistin-susceptible strain (WT) was 7 days compared with 9 days for the colistin-resistant strain (256) (P < 0.0001). In the genomic studies, several mutations were observed in the lpxD genes, leading to the loss of LPS in the colistin-resistant strains. The proteomic studies showed several up- and down-regulated proteins that may be involved in colistin resistance or in a decrease in the resistance profile for several antibiotics.
  
  
  CONCLUSIONS
  This study shows that the mechanism of resistance to colistin by A. nosocomialis is mainly associated with the loss of LPS due to mutations in the lpxD gene, although changes in the expression of some proteins cannot be ruled out. In addition, the acquisition of colistin resistance is related to a decrease in virulence.
authors: ISGlobal, Barcelona Ctr. Int. Health Res. (CRESIB), Hospital Clínic - Universitat de Barcelona, Barcelona, Spain Department of Chemistry and Molecular Pharmacology, Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain.
authors: Xavier
authors: X
authors: Vila-Farrés
authors: ISGlobal, Barcelona Ctr. Int. Health Res. (CRESIB), Hospital Clínic - Universitat de Barcelona, Barcelona, Spain.
authors: Mario
authors: M
authors: Ferrer-Navarro
authors: ISGlobal, Barcelona Ctr. Int. Health Res. (CRESIB), Hospital Clínic - Universitat de Barcelona, Barcelona, Spain.
authors: Anna Elena
authors: AE
authors: Callarisa
authors: ISGlobal, Barcelona Ctr. Int. Health Res. (CRESIB), Hospital Clínic - Universitat de Barcelona, Barcelona, Spain.
authors: Sara
authors: S
authors: Martí
authors: ISGlobal, Barcelona Ctr. Int. Health Res. (CRESIB), Hospital Clínic - Universitat de Barcelona, Barcelona, Spain.
authors: Paula
authors: P
authors: Espinal
authors: Unité de recherche sur les maladies infectieuses et tropicales émergentes (URMITE) CNRS-IRD UMR 6236, IHU Méditerranée Infection, Faculté de Médecine et de Pharmacie, Aix-Marseille-Université, Marseille, France.
authors: Sushim
authors: S
authors: Gupta
authors: Unité de recherche sur les maladies infectieuses et tropicales émergentes (URMITE) CNRS-IRD UMR 6236, IHU Méditerranée Infection, Faculté de Médecine et de Pharmacie, Aix-Marseille-Université, Marseille, France.
authors: Jean-Marc
authors: JM
authors: Rolain
authors: Department of Chemistry and Molecular Pharmacology, Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain Department of Organic Chemistry, University of Barcelona, Barcelona, Spain.
authors: Ernest
authors: E
authors: Giralt
authors: ISGlobal, Barcelona Ctr. Int. Health Res. (CRESIB), Hospital Clínic - Universitat de Barcelona, Barcelona, Spain Department of Clinical Microbiology, CDB, Hospital Clinic, School of Medicine, University of Barcelona, Barcelona, Spain jvila@ub.edu.
authors: Jordi
authors: J
authors: Vila
mesh_terms: D000150:Acinetobacter / Q000187:drug effects* / Q000302:isolation & purification / Q000472:pathogenicity*; D000151:Acinetobacter Infections / Q000382:microbiology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000096:biosynthesis / Q000235:genetics; D017173:Caenorhabditis elegans; D003091:Colistin / Q000494:pharmacology*; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D024881:Drug Resistance, Bacterial; D016680:Genome, Bacterial; D008070:Lipopolysaccharides / Q000378:metabolism*; D009154:Mutation; D020543:Proteome; D012692:Serial Passage; D014774:Virulence; D037521:Virulence Factors / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D008070:Lipopolysaccharides; D020543:Proteome; D037521:Virulence Factors; D003091:Colistin