Pseudomonas aeruginosa encodes the heme acquisition system (Has) as a method of sensing and uptake of extracellular heme in a host environment. In this system, heme is captured by a secreted hemophore, HasA, and delivered to an outer-membrane receptor, HasR. Inhibition of this pathway alters expression of the Has system and the higher-capacity Pseudomonas heme uptake (Phu) system leading to decreased virulence. While some efforts have been made to inhibit the heme binding of HasA, picomolar heme affinity presents a significant competitive challenge. Using a model of the Pseudomonas aeruginosa HasR protein, we have proposed a series of peptide sequences that will bind to HasA, inhibiting the HasA/HasR interaction. Using NMR techniques, computer-aided drug design and development of a high-throughput automated cellular assay, we propose a multi-faceted approach towards the identification of novel HasA binders capable of inhibiting interaction with HasR. This method could lead to the new understanding of the system as well as the development of new antibiotics without the need to penetrate the membranes of gram-negative bacteria.

Identification of inhibitors of the Pseudomonas aeruginosa HasA/HasR protein-protein interaction

255th National Meeting (2018)

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