There has been growing interest in disrupting bacterial virulence mechanisms as a form of
infectious disease control through the use of 'anti-infective' drugs. Pseudomonas aeruginosa is an opportunistic pathogen noted for its intrinsic antibiotic resistance that causes serious
infections requiring new therapeutic options. In this study, an analysis of the P. aeruginosa PAO1 deduced
proteome was performed to identify pathogen-associated
proteins. A computational screening approach was then used to discover
drug repurposing opportunities, i.e. identifying approved drugs that bind and potentially disrupt the pathogen-associated
protein targets. The selective oestrogen receptor modulator
raloxifene, a
drug currently used in the prevention of
osteoporosis and/or invasive
breast cancer in post-menopausal women, was predicted from this screen to bind P. aeruginosa PhzB2. PhzB2 is involved in production of the blue pigment
pyocyanin produced via the
phenazine biosynthesis pathway.
Pyocyanin is toxic to eukaryotic cells and has been shown to play a role in
infection in a mouse model, making it an attractive target for anti-infective
drug discovery.
Raloxifene was found to strongly attenuate P. aeruginosa virulence in a Caenorhabditis elegans model of
infection. Treatment of P. aeruginosa wild-type strains PAO1 and PA14 with
raloxifene resulted in a dose-dependent reduction in
pyocyanin production in vitro;
pyocyanin production and virulence were also reduced for a phzB2 insertion mutant. These results suggest that
raloxifene may be suitable for further development as a therapeutic for P. aeruginosa
infection and that such already approved drugs may be computationally screened and potentially repurposed as novel anti-infective/anti-virulence agents.