Designed Antibiotic Peptides and Mimetics

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The overall goal of this research project is to develop small-molecule antibacterial agents (peptides & mimetics) for use against infectious disease related to biodefense. These novel compounds fall into the bacterial membrane-disintegrating class of agents, and as such their use is not likely to promote development of bacterial resistance. The Aims of the research project are: Aim 1. Optimize bactericidal activity of the amphipathic peptide 12mer SC4. The goal is to identify key amino acids in SC4 that promote antibacterial activity, and to maximize activity with the optimal combination of amino acid side-chains and chemical modifications. Aim 2. Design calixarene-based SC4 mimetics. Amphipathic, non-peptidic compounds based on the calixarene scaffold, and molecular dimensions and surface topology of folded peptide SC4, will be designed, synthesized and tested. Information from Aim 1 will be used to guide mimetic design in Aim 2. Aim 3. Assess biological efficacy of bactericidal agents. First, all compounds made under Aims 1 and 2 will be tested in in vitro assays. The most active compounds from Aims 1 and 2 then will be tested in vivo in mice directly challenged with live bacteria. Finally, the one or two best bactericidal agents will be ADMETassessed for clearance, stability, tissue distribution and toxicity in mice. This research project has so far produced novel bactericidal agents that are effective against bioterrorism agents B. anthracis and Y. pestis, among others, and that may be developed as therapeutics.