| The continual emergence of multidrug resistance in bacteria calls for the development of novel antibiotics in order to treat resistant infections. Traditionally, small molecule antibiotics have been used as treatment for infections. However, the emergence of multidrug resistance in bacteria encompasses every major class of commercially available antibiotics. As the need for antimicrobials capable of combating multidrug resistant bacteria grows, completely new therapeutic paradigms for the treatment of bacterial infections are being explored. This thesis presents one such paradigm in which small- molecule ligands conjugated to gold nanoparticles function as novel antibacterial materials. The goal of this work was to develop the synthetic methods necessary for gold nanoparticle library synthesis and purification, identify gold nanoparticle conjugates capable of inhibiting the growth of various strains of bacteria, determine nanoscale structure-activity relationships (NSAR) for the most active conjugates, and gain insights into the mode of action of these gold nanoparticle conjugates. Gold nanoparticle conjugates capable of inhibiting the growth of various strains of bacteria were identified from an initial 120 member combinatorial library. The activity of the gold nanoparticle conjugates was dependent on the chemical functionalities combined on the surface of the gold nanoparticles. Preliminary studies identified a lead gold nanoparticle conjugate, designated LAL-32, which displayed 99.9% growth inhibition of E. coli at a concentration of 250 nM and a therapeutic index of 400. |
