Development of screening assays and discovery of initial inhibitors of pneumococcal peptidoglycan deacetylase PgdA

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 IC50 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.

Graphical abstractInhibitory compounds of peptidoglycan deacetylase PgdA identified by virtual HTS and confirmed by novel enzyme assay.Figure optionsDownload full-size imageDownload as PowerPoint slide