Molecular Design, Synthesis and Biological Evaluation of Heterocyclic Compounds as Potential Targeted Antimicrobial Agents

Abstract

Abstract The rapid and continuous spread of antimicrobial resistance poses an enormous burden and threat to the global public health, where infections caused by multidrug resistant bacteria are associated with serious morbidity and mortality. The Gram-positive bacterium Staphylococcus aureus is a major cause of both nosocomial and community-acquired infections worldwide. The first methicillin-resistant S. aureus (MRSA) strain was isolated in the United Kingdom in 1961. This resistance phenotype arose through the acquisition of a gene cassette containing mecA, which encoded an altered transpeptidase, penicillin binding protein 2a (PBP2a), that demonstrated low binding affinity to most commercially available β-lactam antibiotics and was capable of cross-linking the peptidoglycan chains of the cell wall when other transpeptidases were inhibited by β-lactams. Since 1990 and up till today, MRSA infections presented a stressing global problem and the development of new antimicrobial agents to combat MRSA infections is of utmost importance. Targeting the key resistance enzyme, penicillin binding protein 2a, with small molecules is a promising therapeutic approach to tackle MRSA infections and was proved successful by the approval of the β-lactam antibiotics, ceftobiprole and ceftaroline. Our research objectives were to design, synthesize and biologically evaluate new inhibitors targeting MRSA infections via inhibition of the mutant PBP2a.