- Fall 2018
- George & Winifred Clark Professor, University of Notre Dame
- Howard J. Schaeffer Distinguished Professor of Chemistry, North Carolina State University
- Professor, North Carolina State University
- Associate Professor, North Carolina State University
- Assistant Professor, North Carolina State University
- Research Associate, The Scripps Research Institute
- Postdoctoral Scholar, The California Institute of Technology
- Ph.D. in Chemistry, Columbia University
- M.Phil. in Chemistry, Columbia University
- M.A. in Chemistry, Columbia University
- B.S. in Chemistry, University of California - Davis
- North Carolina State University Faculty Scholar
- NCSU Entrepreneur of the Year
- Industrial Innovator of the Year, Southeastern Region, ACS
- Sigma Xi Faculty Research Award
The Melander lab is interested broadly in applying the principles of synthetic organic chemistry and microbiology to deliver novel molecules that address problems associated with failure in antibiotic therapy for the treatment of bacterial infections. Specifically, we are interested in developing novel approaches to combat biofilm-based infections that typically give rise to chronic infections (such as those found in Cystic Fibrosis patients, indwelling medical devices, and diabetic ulcers), as well as acute bacterial infections caused by multi-drug resistant pathogens.
A biofilm is defined as a surface attached community of bacteria encased in an extracellular matrix. Biofilms are typically 100-1000-fold more resistant to antibiotics and are recalcitrant to clearance by the host immune response. To address this problem, we are investigating the effects that simple structural motifs found 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.
Multi-drug Resistant Bacteria
The rise of multi-drug resistant pathogens is threatening the vast medical advancements made possible by antibiotics over the last 70+ years. Surgery, premature infant care, cancer chemotherapy, care of the critically ill, and transplantation medicine to name a few fields are feasible only with the existence of effective antibiotic therapy. To address this issue, the Melander lab is currently pursing two distinct yet complementary avenues. The first focuses on new chemical matter that give rise to narrow spectrum antibiotic profiles (both small molecules and nanoparticles) that are potentially less damaging to commensal flora and less susceptible to resistance evolution. The second avenue relies upon an adjuvant approach, in which a small molecule that targets resistance mechanisms is paired with currently approved antibiotics. This latter approach is underpinned by the discovery that a certain sub-set of our 2-aminoimidazole library is able to render multi-drug resistant bacterial strains susceptible to various classes of 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 models of infection.
- Barker, W. T.; Martin, S. E.; Chandler, C. E.; Nguyen, T. V.; Harris, T. L.; Goodell, C.; Melander, R. J.; Doi, Y.; Ernst, R. K.; Melander, C. "Small molecule adjuvants that suppress both chromosomal and mcr-1 encoded colistin-resistance and amplify colistin efficacy in polymyxin-susceptible bacteria." Bioorg. Med. Chem. 2017, 25, 5749-5753.
- Milton, M. E.; Allen, C. L.; Feldmann, E. A.; Bobay, B. G.; Jung, D. K.; Stephens, M. D.; Melander, R. J.; Theisen, K. E.; Zeng, D.; Thompson, R. J.; Melander, C.; Cavanagh, J. "Structure of the Francisella response regulator QseB receiver domain, and characterization of QseB inhibition by antibiofilm 2-aminoimidazole-based compounds." Mol. Microbiol. 2017, 106, 223-235.
- Melander, R. J.; Melander, C. "The Challenge of Overcoming Antibiotic Resistance: An Adjuvant Approach?" ACS Infectious Diseases 2017, 3, 559-563.
- Byrne-Nash, R.; Lucero, D. M.; Osbaugh, N. A.; Melander, R. J.; Melander, C.; Feldheim, D. L. "Probing the Mechanism of LAL-32, a Gold Nanoparticle-Based Antibiotic Discovered through Small Molecule Variable Ligand Display." Bioconjug. Chem. 2017, 28, 1807-1810.
- Garcia, S. S.; Blackledge, M. S.; Michalek, S.; Su, L.; Ptacek, T.; Eipers, P.; Morrow, C.; Lefkowitz, E. J.; Melander, C.; Wu, H. "Targeting of Streptococcus mutans Biofilms by a Novel Small Molecule Prevents Dental Caries and Preserves the Oral Microbiome." J. Dent. Res. 2017, 96, 807-814.
- Nguyen, T. V.; Blackledge, M. S.; Lindsey, E. A.; Minrovic, B. M.; Ackart, D. F.; Jeon, A. B.; Obregon-Henao, A.; Melander, R. J.; Basaraba, R. J.; Melander, C. "The Discovery of 2-Aminobenzimidazoles That Sensitize Mycobacterium smegmatis and M. tuberculosis to beta-Lactam Antibiotics in a Pattern Distinct from beta-Lactamase Inhibitors." Angew. Chem. Int. Ed. 2017, 56, 3940-3944.