Discovery of novel Pneumococcal surface adhesin A (PsaA) inhibitors using fragment‐based drug design

Streptococcus pneumoniae is a leading cause of pneumococcal infections, especially in young children in developing countries. Treatment relies heavily on β‐lactam antibiotics, however, rapid emergence of multidrug‐resistant strains of S. pneumoniae over the past two decades has shifted the focus towards identification of novel drug targets. Pneumococcal surface adhesin A (PsaA) is one such drug target, found on the cell surface of S. pneumoniae . It functions as surface adhesin, as well as substrate binding protein, facilitating acquisition of Mn 2+ , an essential cation that plays an important role in protecting S. pneumoniae from reactive oxygen species produced during oxidative stress. PsaA is essential for bacterial survival and is an important virulence factor, rendering it a promising target for antibiotic development. To design novel PsaA inhibitors, we used a combination of de novo fragment‐based drug discovery (FBDD) 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 their potency while maintaining their ligand‐efficiency and physicochemical properties. The optimized hits were validated using cell‐based assay and molecular dynamics simulations. We found that virtual screening substantially augmented FBDD approaches, leading to the identification of novel PsaA inhibitors.