title: Development of screening assays and discovery of initial inhibitors of pneumococcal peptidoglycan deacetylase PgdA.
abstract: The essential cell wall peptidoglycan is the target of several components of the innate immune system and its disruption results in lysis of invading bacteria. The pathogen Streptococcus pneumoniae produces a peptidoglycan N-acetylglucosamine deacetylase, PgdA, to modify the peptidoglycan structure. The activity of PgdA contributes to the bacteria's resistance to lysozyme, which is an important antimicrobial factor of the human innate immune system. In this study we report on the activity of PgdA against natural and artificial substrates. We have also established a virtual high-throughput screening and a new enzyme assay to search for compounds inhibiting PgdA. Two compounds with IC(50) values in the micromolar range have been identified and they could serve as leads for the search of inhibitors of PgdA, an important pneumococcal virulence factor.
authors.affiliation: Centre for Bacterial Cell Biology, Institute for Cell and Molecular Biosciences, Newcastle University, United Kingdom.
authors.forename: Nhat Khai
authors.initials: NK
authors.lastname: Bui
authors.forename: Samo
authors.initials: S
authors.lastname: Turk
authors.forename: Stephan
authors.initials: S
authors.lastname: Buckenmaier
authors.forename: Flint
authors.initials: F
authors.lastname: Stevenson-Jones
authors.forename: Benjamin
authors.initials: B
authors.lastname: Zeuch
authors.forename: Stanislav
authors.initials: S
authors.lastname: Gobec
authors.forename: Waldemar
authors.initials: W
authors.lastname: Vollmer
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D003198:Computer Simulation; D017076:Computer-Aided Design; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D057166:High-Throughput Screening Assays; D054884:Host-Pathogen Interactions; D006801:Humans; D020128:Inhibitory Concentration 50; D013296:Streptococcus pneumoniae / Q000187:drug effects* / Q000201:enzymology / Q000472:pathogenicity; D013329:Structure-Activity Relationship; D037521:Virulence Factors / Q000037:antagonists & inhibitors*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D037521:Virulence Factors; D000581:Amidohydrolases; C411846:pgdA protein, Streptococcus pneumoniae