Structure-activity relationship of the cinnamamide family of antibiotic potentiators for methicillin-resistant Staphylococcus aureus (MRSA).

Methicillin-resistant Staphylococcus aureus (MRSA) is a global public health threat. MRSA has evolved a complex set of biochemical processes that mobilize the organism for inducible resistance on challenge by β-lactam antibiotics. Interfering pharmacologically with this machinery has the potential to reverse the β-lactam-resistance phenotype, whereby susceptibility to obsolete antibiotics would be restored. We describe herein our discovery of one class of such agents, the cinnamamide family of antibiotic potentiators. A hit compound of the class (compound 1) showed modest potentiation of the activity of oxacillin, a penicillin antibiotic, against an MRSA strain. A total of 50 analogues of compound 1 were prepared and screened. Seven of these compounds showed more dramatic potentiation of the antibacterial activity, which lowered the minimal-inhibitory concentrations (MICs) for the antibiotic by as much as 64- to 128-fold.