The goal of this project is the synthesis of macrocyclic peptides that trap Holliday Junctions (HJ) in bacteria, and their subsequent evaluation as potential antibiotics. The HJ is an intermediate during site-specific recombination, a DNA repair mechanism. Trapping the HJ shuts down DNA repair in bacteria. Because the HJ would be a unique therapeutic target, compounds that trap this intermediate may effectively kill resistant strains of bacteria. This mechanism is reminiscent of the quinolone/fluoroquinolone class of antibiotics, which stabilize a normally transient intermediate, thereby killing bacteria. Outlined are two specific aims designed to accomplish our goal. The first specific aim describes the synthesis of a new class of compounds, C-2 symmetrical macrocyclic peptides, which were designed from lead structures. These lead structures are linear dodecapeptides that exhibit potent bactericidal activity by trapping the HJ. 1,2 The second specific aim (SA2) describes the evaluation of these compounds as potential antibiotics using bacterial growth assays and biochemical assays. Preliminary data demonstrates the success of the proposed strategy, where our macrocyclic compounds trap the HJ in the biochemical assays and demonstrate some antibiotic activity in cell growth assays. Care has been taken to ensure the goals can be realistically accomplished in the two-year time frame for this proposal. These pilot studies are intended to demonstrate the feasibility of this project. Once the viability of the proposed idea has been clearly established, we will submit a more in-depth and expanded proposal. ? ?
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|Rodriguez, Rodrigo A; Pan, Po-Shen; Pan, Chung-Mao et al. (2007) Synthesis of second-generation sansalvamide A derivatives: novel templates as potential antitumor agents. J Org Chem 72:1980-2002|
|Styers, Thomas J; Kekec, Ahmet; Rodriguez, Rodrigo et al. (2006) Synthesis of Sansalvamide A derivatives and their cytotoxicity in the MSS colon cancer cell line HT-29. Bioorg Med Chem 14:5625-31|
|Pan, Po-Shen; Curtis, Fiona A; Carroll, Chris L et al. (2006) Novel antibiotics: C-2 symmetrical macrocycles inhibiting Holliday junction DNA binding by E. coli RuvC. Bioorg Med Chem 14:4731-9|