Synthesis, Anti-Methicillin-resistant S. aureus (MRSA) Evaluation, Quantitative Structure-Activity Relationship and Molecular Modeling Studies of Some Novel Bis-indoles as Prospective MRSA Pyruvate Kinase Inhibitors

Background: MRSA is a gram positive pathogen resistant to methicillin and other betalactam antibiotics, including penicillin, oxacillin, and declooxacillin. Statistical data suggest that as many as 19,000 people per year die from MRSA in the USA. Methods: Prudent use of existing drugs, coupled with the development of new antibacterial agents has been suggested as a way to combat the public health burden, posed by MRSA. In this work, about 60 compounds of bis-indoles (diindolylmethanes and diindolylmethenes) were synthesized and screened as antibacterial agents against S. aureus and methicillin-resistant S. aureus (MRSA). The quantitative structure-activity relationships (QSAR) of the compounds were also carried out in this work. Results: Good numbers of the compounds appear to be good antibiotic candidates against MRSA. The modelled complexes of S. aureus pyruvate kinase (PK) and the active compounds indicate that these bis-indole candidates fit perfectly in the binding groove between two monomers of PK. The compounds are predicted to have H-bond and steric interactions with important amino acid residues. Conclusion: The current study may lead to discover a new prospective of anti-MRSA candidates.