Optimization and mechanistic studies of psammaplin A type antibacterial agents active against methicillin-resistant Staphylococcus aureus (MRSA)

As described in the preceding article, utilizing a novel combinatorial disu lfide exchange strategy, a library of psammaplin A (1) analogues was constr ucted and screened for antibacterial activity leading to the identification of a collection of diverse lead compounds. These combinatorial leads were subsequently refined, through parallel synthesis, to afford a series of hig hly potent antibacterial agents (e.g. 17. 57, 58, 69, and 70). some possess ing greater than 50-fold higher activities than the natural product. Evalua tion of the selectivity and serum binding properties of some of the most pr omising compounds and preliminary studies directed at deciphering the mecha nism of action of this novel class of antibacterial agents are also include d.