title: Resistance phenotypes mediated by aminoacyl-phosphatidylglycerol synthases.
abstract: The specific aminoacylation of the phospholipid phosphatidylglycerol (PG) with alanine or with lysine catalyzed by aminoacyl-phosphatidylglycerol synthases (aaPGS) was shown to render various organisms less susceptible to antibacterial agents. This study makes use of Pseudomonas aeruginosa chimeric mutant strains producing lysyl-phosphatidylglycerol (L-PG) instead of the naturally occurring alanyl-phosphatidylglycerol (A-PG) to study the resulting impact on bacterial resistance. Consequences of such artificial phospholipid composition were studied in the presence of an overall of seven antimicrobials (β-lactams, a lipopeptide antibiotic, cationic antimicrobial peptides [CAMPs]) to quantitatively assess the effect of A-PG substitution (with L-PG, L-PG and A-PG, increased A-PG levels). For the employed Gram-negative P. aeruginosa model system, an exclusive charge repulsion mechanism does not explain the attenuated antimicrobial susceptibility due to PG modification. Additionally, the specificity of nine orthologous aaPGS enzymes was experimentally determined. The newly characterized protein sequences allowed for the establishment of a significant group of A-PG synthase sequences which were bioinformatically compared to the related group of L-PG synthesizing enzymes. The analysis revealed a diverse origin for the evolution of A-PG and L-PG synthases, as the specificity of an individual enzyme is not reflected in terms of a characteristic sequence motif. This finding is relevant for future development of potential aaPGS inhibitors.
authors.affiliation: Institute of Microbiology, Technische Universität Braunschweig, Braunschweig, Germany.
authors.forename: Wiebke
authors.initials: W
authors.lastname: Arendt
authors.forename: Stefanie
authors.initials: S
authors.lastname: Hebecker
authors.forename: Sonja
authors.initials: S
authors.lastname: Jäger
authors.forename: Manfred
authors.initials: M
authors.lastname: Nimtz
authors.forename: Jürgen
authors.initials: J
authors.lastname: Moser
mesh_terms: D000409:Alanine / Q000378:metabolism*; D019881:Aminoacyltransferases / Q000235:genetics / Q000378:metabolism*; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D024881:Drug Resistance, Bacterial; D008239:Lysine / Q000378:metabolism*; D008826:Microbial Sensitivity Tests; D010715:Phosphatidylglycerols / Q000378:metabolism*; D010802:Phylogeny; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D010715:Phosphatidylglycerols; D011994:Recombinant Proteins; D019881:Aminoacyltransferases; C562342:alanyl-phosphatidylglycerol synthase, Pseudomonas aeruginosa; D008239:Lysine; D000409:Alanine