Abstract
Streptococcus pneumoniae is a leading cause of life-threatening bacterial infections, especially in young children in developing countries. Pneumococcal infections can be treated with β-lactam antibiotics, but rapid emergence of multidrug-resistant strains of S. pneumoniae over the past two decades has emphasized the need to identify novel drug targets. Pneumococcal surface antigen A (PsaA) is one such target, found on the cell surface of S. pneumoniae. It functions as a high-affinity substrate-binding protein, facilitating acquisition of Mn(2+), which has an important role in protecting S. pneumoniae from reactive oxygen species and, hence, oxidative stress. Consequently, PsaA is essential for bacterial survival and an important virulence factor, which makes it a promising target for antibiotic drug development. To design novel PsaA inhibitors, we used a combination of de novo fragment-based drug discovery and in silico virtual screening methods. We profiled a collection of low molecular weight compounds that were selected based on their structural diversity and ability to bind to apo-PsaA in a virtual docking experiment. The screening resulted in two initial hits that were further optimized by structural variation to improve ...Continue Reading
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