title: genetic determinants of intrinsic colistin tolerance in Acinetobacter baumannii.
abstract: Acinetobacter baumannii is a leading cause of multidrug-resistant infections worldwide. This organism poses a particular challenge due to its ability to acquire resistance to new antibiotics through adaptation or mutation. This study was undertaken to determine the mechanisms governing the adaptability of A. baumannii to the antibiotic colistin. Screening of a transposon mutant library identified over 30 genes involved in inducible colistin resistance in A. baumannii. One of the genes identified was lpsB, which encodes a glycosyltransferase involved in lipopolysaccharide (LPS) synthesis. We demonstrate that loss of LpsB function results in increased sensitivity to both colistin and cationic antimicrobial peptides of the innate immune system. Moreover, LpsB is critical for pathogenesis in a pulmonary model of infection. Taken together, these data define bacterial processes required for intrinsic colistin tolerance in A. baumannii and underscore the importance of outer membrane structure in both antibiotic resistance and the pathogenesis of A. baumannii.
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: M Indriati
authors.initials: MI
authors.lastname: Hood
authors.forename: Kyle W
authors.initials: KW
authors.lastname: Becker
authors.forename: Christelle M
authors.initials: CM
authors.lastname: Roux
authors.forename: Paul M
authors.initials: PM
authors.lastname: Dunman
authors.forename: Eric P
authors.initials: EP
authors.lastname: Skaar
mesh_terms: D000151:Acinetobacter Infections / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000382:microbiology*; D040981:Acinetobacter baumannii / Q000187:drug effects* / Q000235:genetics* / Q000276:immunology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000276:immunology / Q000494:pharmacology; D023181:Antimicrobial Cationic Peptides / Q000235:genetics / Q000276:immunology; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology; D003091:Colistin / Q000276:immunology / Q000494:pharmacology*; D024901:Drug Resistance, Multiple, Bacterial; D005260:Female; D016695:Glycosyltransferases / Q000235:genetics / Q000276:immunology; D007108:Immune Tolerance / Q000235:genetics / Q000276:immunology; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology; D008070:Lipopolysaccharides / Q000235:genetics / Q000276:immunology; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D008364:Mannosyltransferases / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009154:Mutation / Q000276:immunology; D011014:Pneumonia / Q000235:genetics / Q000276:immunology / Q000382:microbiology
chemical_list: D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D001426:Bacterial Proteins; D008070:Lipopolysaccharides; D016695:Glycosyltransferases; C422469:LpsB protein, bacteria; D008364:Mannosyltransferases; D003091:Colistin