Amphipathic β-Strand Mimics as Potential Membrane Disruptive Antibiotics

In recent years, there have been increasing numbers of bacterial strains emerging that are resistant to the currently available antibiotics. In the search for new antibiotics, attention has been focused on natural antimicrobial peptides that act by selectively disrupting the membranes of bacterial cells, a mechanism that is thought to be nonconducive to the development of resistance. It is desirable to mimic the structures and activities of these peptides while introducing properties Such as resistance to proteolytic degradation, which make molecules more ideal for development as drugs, Described here is the design and synthesis of beta-strand mimetic oligomers based on alternating alpha-amino acids and azacyclohexenone units that segregate cationic lysine and hydrophobic valine side chains on opposite faces of the beta-strand. H-1 NMR dilution studies demonstrated that despite the incorporation of alternating D- and L-amino acids in order to obtain facial amphiphilicity, these oligomers are capable of dimerizing to beta-sheet mimics in it manner similar to the oligomers containing all L-amino acids. The ability of the molecules to disrupt phospholipid vesicles mimicking the membranes of both bacterial and mammalian cells was investigated using a fluorescent, dye leakage assay, Several of the oligomers were found to exhibit activity and selectivity For the bacterial over mammalian membranes. Overall, these studies demonstrate the promise of this class of molecules for the development of a new, potential antibiotics and provide information on the structural features that are important for activity.