Postdoctoral, The Scripps Research Institute, 2002 - 2004 Lead Scientist, Xencor, 2001-2002 Postdoctoral, California Institute of Technology,1998 - 2001 Ph. D., Organic Chemistry, Columbia University, 1998 M. Phil., Organic Chemistry, Columbia University, 1998 M. A., Organic Chemistry, Columbia University, 1995 B. S., Chemistry, University of California, Davis, 1994

Bio-organic Chemistry

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, Margolis 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.

Dean, S.N., Brackett, C.M., Melander, R.J., Melander, C., Cavanagh, J., and van Hoek, M.L., Small molecule suppression of virulence in Francisella novicida. Submitted Richardson, M.A., Furlani, R.E., Podell, B.K., Ackart, D.F., Haugen, J.D., Melander, R.J., Melander, C., and Basaraba, R.J. Inhibition and Breaking of Advanced Glycation End-Products with Bis-2-Aminoimidazole Derivatives. Tetrahedron Letters (Harry Wasserman edition), Accepted. Wahome, P.G., Beauchesne, K.R., Cato-Pedone, A., Cavanagh, C., Melander, C., Zimba, P., and Moeller, P.D.R. Augmenting Anti-Cancer Natural Products with a Small Molecule Adjuvant. Marine Drugs, Accepted. Gifford, J.C., Bresee, J., Carter, C.J., Wang, G., Melander, R., Melander, C., and Feldheim, D.L. Thiol-Modified Gold Nanoparticles for the Inhibition of M. smegmatis. Chemical Communications, accepted. Stowe, S.D., Thompson, R.J., Peng, L., Su, Z., Blackledge, M.S., Coe, W.H., Johannes, E., Lapham, V.K., Mackenzie, J., Melander, C., and Cavanagh, J. Membrane-Permeabilizing Activity of Reverse-Amide 2-Aminoimidazole Antibiofilm Agents Against Gram-Negative Pathogen, Acinetobacter baumannii. Current Drug Delivery, accepted. Brackett, C.M., Melander, R.J., An, I.H., Krisnamurthy, A., Thompson, R.J., Cavanagh, J., and Melander, C. Small Molecule Suppression of ß-Lactam Resistance in Multi-drug Resistant Gram-negative Pathogens. Journal of Medicinal Chemistry, accepted. Melander, R.J. and Melander, C. Innovative Strategies for Combating Biofilm-based Infections (In Biofilm-Based Healthcare-Associated Infections, Springer) Wright, C.J., Wu, H., Melander, R.J., Melander, C, and Lamont, R.J. Disruption of Heterotypic Community Development by Porphyromonas gingivalis with Small Molecule Inhibitors. Molecular Oral Microbiology, accepted Melander, R.J., Minvielle, M.J., and Melander, C. Controlling Bacterial Behavior with Indole-Containing Natural Products and Derivatives (invited review). Tetrahedron, accepted. Ackart, D.F., Lindsey, E.A., Podell, B.K., Melander, R.J., Basaraba, R.J., and Melander, C. In vitro Reversal of Mycobacterium tuberculosis Drug Resistanceby 2-Aminoimidazole Based Small Molecules. FEMS Pathogens and Disease, accepted. Ackart, D.F., Parks, Q.M., Kirk, N.M., Podell, B.K., Melander, C., Orme, I.M., Leid, J.G., Nick, J.A., and Basaraba, R.J. Expression of Antimicrobial Drug Tolerance by Attached Communities of Mycobacterium tuberculosis. FEMS Pathogens and Disease, accepted. Worthington, R.J, Richards, J.J., and Melander, C. Non-Microbicidal Control of Bacterial Biofilms with Small Molecules. Anti-Infective Agents, 2014, 12 (1), 120-38. Bresee, J., Bond, C.M., Worthington, R.J., Smith, C.A., Carter, C.J., Simpson, C.A., Wang, G., Hartman, J., Osbaugh, N.A., Melander, C., and Feldheim, D.L. Nanoscale Structure-Activity Relationships, Mode of Action, and Biocompatibility of Gold Nanoparticle Antibiotics. Journal of the American Chemical Society, 2014, 136 (14), 5295-5300. Harris, T.L., Worthington, R.J., Hittle, L.E., Zurawski, D.V., Ernst, R.K., and Melander, C. Small Molecule Downregulation of PmrAB Reverses Lipid A Modification and Breaks Colistin Resistance. ACS Chemical Biology, 2014, 9 (1), 127-7. Minvielle, M.J., Eguren, K., and Melander, C. Highly Active Modulators of Indole Signaling to Alter Pathogenic Behavior in Gram-Negative and Gram-Positive Bacteria. Chemistry: A European Journal, 2013, 19 (51), 17595-602. Blackledge, M.S., Worthington, R.J., and Melander, C. Biologically-Inspired Strategies for Combating Bacterial Biofilms. Current Opinion in Pharmacology, 2013, 13 (5), 699-706. Minvielle, M.J., Bunders, C.A., and Melander, C. Indole/triazole Conjugates are Selective Inhibitors and Inducers of Bacterial Biofilms. MedChemComm, 2013, 4 (6), 916-919. Worthington, R.J. and Melander, C. Overcoming Resistance to β-Lactam Antibiotics (JOCSynopsis). Journal of Organic Chemistry, 2013, 78 (9), 4207-4213. Blackledge, M.S. and Melander, C. Programmable DNA-binding Small Molecules. Bioorganic and Medicinal Chemistry, 2013, 21 (20), 6101-14.

Worthington, R.J., Blackledge, M.S., and Melander, C. Small Molecule Inhibition of Bacterial Two-Component Systems to Combat Antibiotic Resistance and Virulence. Future Medicinal Chemistry, 2013, 5 (11), 1265-1284.