Grant: Operating Grant

Aminoglycoside antibiotics have been used clinically for decades as potent antibiotics to fight bacterial infections. Although aminoglycosides exhibit potent bactericidal activity, their widespread use has been compromised by toxicity and resistance. The rapid emergence of aminoglycoside antibiotics-resistant strains has instigated research efforts to develop modified aminoglycoside antibiotics that can delay or avoid acquired resistance by pathogenic bacteria. Previous work in our laboratory has shown that amphiphilic aminoglycoside antibiotics that combine the structural features of aminoglycosides and polycationic amphiphiles form a novel class of hybrid antibiotics that restore activity against clinically relevant aminoglycoside-resistant and multi-drug resistant bacteria. Cell-based assays demonstrate that most amphiphilic aminoglycosides display little to no cytotoxicity at their minimal inhibitory concentrations. In this proposal we plan to extend our preliminary work to other types of amphiphilic aminoglycoside antimicrobials. Structure activity relationships and toxicological evaluation will reveal crucial information for lead optimization. The most active and least toxic compounds will undergo in vivo testing in a mouse model. Another set of experiments will explore the potential modes of action and assess the probability of resistance development. The data obtained in this study will likely lead to the discovery of novel antibacterials with low toxicity and novel or combined modes of action and delayed resistance development.