Development of new antimicrobial compounds is urgently needed as bacteria evolve resistance to the antibiotics of last resort. The long-term objective of this proposal is to identify new carbohydrate-based compounds that bind to the small ribosomal subunit and specifically alter bacterial translation. Five hundred new aminoglycosides will be prepared using solution and solid-phase methods. Their binding affinity, specificity, and location on a 27 nucleotide RNA model of the consensus bacterial A site about determined using electrospray ionization mass spectrometry. Compounds that bind with greater than 500 nM affinity and greater than 10x specificity will be moved into translation assays and their MIC values will be determined pathogenic strains. The pharmacokinetic and toxicological properties of the best compounds will be measured and improved in a Phase II application. PROPOSED COMMERCIAL APPLICATION: New families of antimicrobial compounds are needed to offset developing drug resistance. Identification and development of a new class of antimicrobial compounds based on a conserved RNA target would generate a significant market opportunity. Therapeutic targets could include pneumococci, enterococci, and tuberculosis - especially their drug-resistant strains.
