SBIR-STTR Award

Rapid and widespread emergence of antibiotic-resistant pathogens creates an urgent need for concerted approaches towards novel antibacterials. The long-term objective of this proposal is the development of synthetic antibiotics that overcome known resistance mechanisms. Structure-based molecular design in combination with leading-edge synthetic chemistry and screening methods will be used to exploit emerging structural data on the bacterial ribosome, a proven target for antibiotics. Selected natural antibiotics will serve as paradigms for the design of libraries consisting of novel aminoglycoside derivatives and thiopeptide mimetics. Crystal structures of the ribosomal target sites and computational analysis of their molecular recognition by ligands will aid the compound design effort. Compound libraries will be synthesized using convergent routes. Screening of compound libraries for their activity on the ribosomal target will be performed by fluorescence assays that have been developed for RNA targets at Anadys Pharmaceuticals. The integration of structure-based ligand design for the ribosome, one of the most complex macromolecular assemblies, with efficient synthesis of structurally complex ligands and their screening represents a formidable challenge. The benefit of the proposed research will extend beyond the immediate antibiotic discovery effort by providing the proof of principle for RNA as a feasible target for synthetic drugs. PROPOSED COMMERCIAL APPLICATIONS: The proposed research is aimed at discovering lead compounds that are potential antibiotics for the therapy of bacterial infections, especially for pathogens with resistance against existing antibiotics.

Thesaurus Terms:
antibiotic, biomimetics, biotherapeutic agent, drug design /synthesis /production, drug discovery /isolation, peptide chemical synthesis, ribosome aminoglycoside antibiotic, bacterial RNA, combinatorial chemistry, drug screening /evaluation, guanine nucleotide binding protein, immunologic substance development /preparation, ligand, peptide library, peptide structure, ribosomal RNA, synthetic peptide Escherichia coli, biotechnology, fluorescent dye /probe, high performance liquid chromatography, high throughput technology, immunologic assay /test, molecular dynamics, nucleic acid sequence

Rapid and widespread emergence of antibiotics-resistant pathogens creates an urgent need for concerted approaches towards novel antiinfectives. The long-term objective of this proposal is the development of novel potent antibacterials that target the ribosomal RNA (rRNA) of antibiotics-resistant bacteria. Specifically, a lead series of small molecules that recognize the ribosomal decoding-site RNA (A-site) will be developed to select an antibacterial drug candidate by iterative rounds of synthesis and testing for target binding, inhibition of protein synthesis and bacterial growth. The ribosomal A-site constitutes a prime target for antibiotics, validated by the naturally occurring aminoglycosides and a novel series of chemically unrelated antibacterials that we have discovered recently. Rational structure-based design along with multi-dimensional drug optimization, using testing data from a range of biochemical and biological assays, will allow us to develop a novel class of antibiotics that are not susceptible to known bacterial resistance mechanisms. These novel antibacterial A-site ligands will constitute the first class of antibiotics that has been developed by a rational approach of drug discovery specifically directed at an RNA component of the bacterial ribosome.

Thesaurus Terms:
antibacterial agent, chemical structure function, combinatorial chemistry, drug design /synthesis /production, drug discovery /isolation, drug screening /evaluation, pharmacokinetics, ribosomal RNA antibiotic, bacteria infection mechanism, bacterial RNA, biological model, chemical stability, crystallization, cytotoxicity, drug resistance, gram negative bacteria, gram positive bacteria, ligand, microorganism growth, three dimensional imaging /topography cell line, chemical synthesis, high throughput technology, laboratory mouse