Penicillin binding protein 2a (PbP 2a) expression accounts for the insusceptibility of methicillin-resistant Staphylocuccus aureus (MRSA) to β-lactam antibiotics. Here we employed computational strategies to challenge PbP 2a with series of fifty-five 'ala-ala' and 'ala-pro' sulphonamide-dipeptides. Binding stability of two compounds (labeled: 10i and 10n) with theoretical Ki in nM and µM ranges, for PbP 2a active and allosteric sites respectively, were investigated using molecular dynamics simulations. In addition, the results of the sensitivity of four strains of MRSA for compounds 10i and 10n obtained revealed the compounds at 10 µg/ml caused two isolates (S4 and S10) to revert to being susceptible. Finally, a reliable binding conformations of both compounds in the two binding sites of PbP 2a are described to provide rationale for structure-activity optimization of this series.Communicated by Ramaswamy H. Sarma.
Keywords: MRSA; PbP 2a; Sulphonamides; binding mode prediction; molecular docking; molecular dynamics simulation; peptides.