title: Aminoarabinose is essential for lipopolysaccharide export and intrinsic antimicrobial peptide resistance in Burkholderia cenocepacia(†).
abstract: One common mechanism of resistance against antimicrobial peptides in Gram-negative bacteria is the addition of 4-amino-4-deoxy-L-arabinose (L-Ara4N) to the lipopolysaccharide (LPS) molecule. Burkholderia cenocepacia exhibits extraordinary intrinsic resistance to antimicrobial peptides and other antibiotics. We have previously discovered that unlike other bacteria, B. cenocepacia requires L-Ara4N for viability. Here, we describe the isolation of B. cenocepacia suppressor mutants that remain viable despite the deletion of genes required for L-Ara4N synthesis and transfer to the LPS. The absence of L-Ara4N is the only structural difference in the LPS of the mutants compared with that of the parental strain. The mutants also become highly sensitive to polymyxin B and melittin, two different classes of antimicrobial peptides. The suppressor phenotype resulted from a single amino acid replacement (aspartic acid to histidine) at position 31 of LptG, a protein component of the multi-protein pathway responsible for the export of the LPS molecule from the inner to the outer membrane. We propose that L-Ara4N modification of LPS provides a molecular signature required for LPS export and proper assembly at the outer membrane of B. cenocepacia, and is the most critical determinant for the intrinsic resistance of this bacterium to antimicrobial peptides.
authors: Centre for Human Immunology, Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada.
authors: Mohamad A
authors: MA
authors: Hamad
authors: Flaviana
authors: F
authors: Di Lorenzo
authors: Antonio
authors: A
authors: Molinaro
authors: Miguel A
authors: MA
authors: Valvano
mesh_terms: D000890:Anti-Infective Agents / Q000494:pharmacology; D001089:Arabinose / Q000031:analogs & derivatives* / Q000737:chemistry; D001692:Biological Transport / Q000235:genetics / Q000502:physiology; D057508:Burkholderia cenocepacia / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D024881:Drug Resistance, Bacterial / Q000235:genetics; D008070:Lipopolysaccharides / Q000737:chemistry* / Q000378:metabolism*; D008555:Melitten / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D011112:Polymyxin B / Q000494:pharmacology
chemical_list: D000890:Anti-Infective Agents; D008070:Lipopolysaccharides; C016982:aminoarabinose; D008555:Melitten; D001089:Arabinose; D011112:Polymyxin B