The increasing prevalence of multidrug-resistant bacteria in the clinic necessitates new anti-infective strategies. Recently, inhibitors of virulence factors have come into focus as an alternative to conventional antibiotics. Pseudomonas aeruginosa, a pathogen that causes problematic infections in the hospital as well as in patients with cystic fibrosis, produces several virulence factors that can be targeted by such an approach. Knockout mutant experiments have shown that strains deficient of the redox active virulence factor pyocyanin exhibit reduced virulence. Therefore, one of its key biosynthetic enzymes, PhzF, was identified as a potential drug target. In this work, we used published PhzF crystal structures as starting point for structure- and fragment-based drug design. Analyzing the crystal structures, a promising binding pocket was found next to the catalytic center of PhzF. Therefore, derivatives of 2-amino-3-hydroxybenzoic acid, which is known to bind to the active site of PhzF, were generated with a virtual fragment growth approach. Promising compounds were acquired or synthesized and PhzF binding was investigated by X-ray diffraction analysis. The solved crystal structures allowed us to identify PhzF ligands and we could demonstrate new important interactions of these ligands with the binding pocket that can be used for further optimization.

Design of PhzF inhibitors as potential P. aeruginosa antivirulence agents

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