Grant: Proof of Principle Program - Phase I

Aminoglycoside antibiotics have been used clinically for decades as potent antimicrobial agents to fight bacterial infections. Although AAs exhibit potent bactericidal activity, their widespread use has been compromised by dose-related nephrotoxicity and ototoxicity. In addition, the rapid emergence of AA-resistant strains has instigated research efforts to develop modified AA-analogs that can delay or avoid acquired resistance by pathogenic bacteria. Previously, we have developed a technology that enables facile access to structurally diverse aminoglycoside analogs. Using neomycin B and kanamycin A as examples, we have shown that these analogs can restore potent activity against clinically relevant and multi-drug resistant bacteria including AA-resistant MRSA, MRSE, E. coli and Pseudomonas aeruginosa. In vitro toxicity assays show that these analogs have little or no toxicity against mammalian erythrocytes. In this proposal we plan to extend the synthetic work, the antimicrobial in vitro assays and in vitro toxicity assessment to amikacin and tobramycin analogs, the most clinically used aminoglycosides. The most active and least toxic compounds will undergo in vivo efficacy and toxicity testing in mouse protection models. Provided that promising in vivo efficacy and toxicity data are obtained the evaluated drug candidates will be licensed to industry partners to perform clinical trials.