1. Pyrrole Imidazole Alkaloid Derivatives to Control Biofilm Formation. We are investigating the effects that simple structural motifs that are embedded in complex marine natural products have upon biofilm development and maintenance. We have demonstrated that simple derivatives of the natural products bromageliferin and oroidin will inhibit and disperse biofilms from pathogenic bacteria as well as fungi, and mixed species biofilms. We have also established that our 2-aminoimidazole-derived anti-biofilm agents are non-toxic to red blood cells, mammalian cell lines, and model organisms. The mechanistic basis by which these compounds inhibit and disperse biofilms as well as the effect these compounds have in vivo are being pursued. We are also interested in developing synthetic approaches to access any predefined substitution pattern on the 2-aminoimidazole scaffold.

2. Small Molecule Control of Antibiotic Resistance. We have recently discovered that a certain sub-set of our 2-aminoimidazole library are able to both to inhibit/disperse microbial biofilms and render multi-drug resistant bacterial strains (MDR) susceptible to conventional antibiotics. We are currently probing the mechanistic basis of this activity, augmenting activity through analogue synthesis, and exploring the in vivo potential of these compounds in animal and plant models of infection.

3. Indole Signaling. Indole is one of the putative universal signals for bacteria, controlling bacterial behavior such as biofilm formation, virulence production, and acid tolerance. We are currently developing probes of indole signaling based upon the flustramine class of natural products and employing these small molecules to probe multi-species interactions within a biofilm and to further deconvolute the basis of indole signaling across Gram-positive and Gram-negative bacteria.

4. Multi-Valent Gold Nanoparticles for Biomedical Applications. In collaboration with the Feldheim group and Ackerson group we are exploring the use of multi-valent gold particles for various biomedical appliations. We have demonstrated that we can fabricate particles that will efficiently inhibit HIV-1 infection and are exploring the possibility of using these particles against HIV mutants that are resistant to current anti-HIV therapies. We are also exploring the use of gold nanoparticles as a combinatorial platform for the discovery of novel antibiotics as well as a carrier for delivering drugs across the blood/brain barrier. Recently, we have been investigating the ability to trigger chemical reactions on the gold nanoparticle surface and harness the resulting reactive intermediates for biomedical applications.

5. Medicinal Chemistry. Our group is also involved in various small molecule synthesis projects that seek to optimize the activity of lead scaffolds that are identified through screening efforts. Currently, we are working in collaboration with the Wu and Chen groups at the University of Alabama to develop highly active small molecules that selectively inhibit the RANKL-induced formation of osteoclasts for various bone desorption diseases. We are also involved in optimizing lead compounds for anti-AGE formation with the Basaraba lab at Colorado State University.