Streptococcus pneumoniae (MDRSp) has emerged to be multi-drug resistant to a wide range of antibiotics such as erythromycin and trimethoprim. The Center for Disease Control now lists MDRSp as one of the twelve most serious antibiotic resistance threats. Previous studies have sought to develop new therapies based on existing antibiotics, but these therapies are susceptible to the same resistance that MDRSp has built up. An emerging approach is to find inhibitors of MDRSp pathways, such as riboflavin synthesis that is present only in MDRSp and not in humans. Recently, researchers have elucidated 3,4-dihydroxy-2-butanone-4-phosphate (SpDHBP) synthase that is critical in riboflavin synthesis. This study exploits this new crystal structure and a number of recent advances, such as protein-protein interaction binding pockets and epoxidation site predictions, to screen for compounds. Two inhibitors, N-(3-acetamido-4-methyl-phenyl)-3-(4-fluorophenyl)-1H-pyrazole-4-carboxamide and N-[(1S)-2-[2-fluoro-5-(2-furyl)anilino]-1-methyl-2-oxo-ethyl]cyclobutanecarboxamide, are putative leads with pIC50 values that are greater than many common and currently available antibiotics.
