Antibacterial Benzimidazole-2-Methanamines as Allosteric Modulators of Streptococcus pneumoniae Penicillin-Binding Protein 2x

The allosteric site of penicillin-binding protein 2x (PBP2x), an essential enzyme of cell-wall biosynthesis of Streptococcus pneumoniae, was targeted in virtual screening of >2 M compounds. A benzimidazole-2-methanamine hit emerged, which exhibited a modest minimal-inhibitory concentration (MIC) of 32 mg·L–1. A structure–activity campaign around the structural template resulted in evaluation of 96 compounds, leading to several analogs with MIC of ≤4 mg·L–1. These compounds exhibited a broad-based bactericidal growth inhibition against 31 clinical strains of S. pneumoniae.