Department of Chemistry & Biochemistry

Biography

2018-Present

George & Winifred Clark Professor, University of Notre Dame

2014-2018

Howard J. Schaeffer Distinguished Professor of Chemistry, North Carolina State University

2013-2018

Professor, North Carolina State University

2010-2013

Associate Professor, North Carolina State University

2004-2010

Assistant Professor, North Carolina State University

2002-2004

Research Associate, The Scripps Research Institute

1998-2001

Postdoctoral Scholar, The California Institute of Technology

1998

Ph.D. in Chemistry, Columbia University

1998

M.Phil. in Chemistry, Columbia University

1995

M.A. in Chemistry, Columbia University

1994

B.S. in Chemistry, University of California - Davis

Selected Awards

2014-2018

North Carolina State University Faculty Scholar

2012

NCSU Entrepreneur of the Year

2012

Industrial Innovator of the Year, Southeastern Region, ACS

2009

Sigma Xi Faculty Research Award

Research Interests

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.

Bacterial Biofilms

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.

Recent Publications

• Hoang, K. V.; Woolard, K.; Yang, C.; Melander, C. and Gunn, J. S. "Identification of a Host-Targeted Compound to Control Typhoid Fever" 2022 Microbiology Spectrum, in press. DOI: 10.1128/spectrum.00619-22.
• Woolard, K. J.; Sandala, J. L.; Melander, R. J.; Gunn, J. S. and Melander, C. "Development of Small Molecules that Work Cooperatively with Ciprofloxacin to Clear Salmonella Biofilms in a Chronic Gallbladder Carriage Model" 2022 European Journal of Medicinal Chemistry, 232, 114203. DOI: 10.1016/j.ejmech.2022.114203.
• Belardinelli, J. M.; Li, W.; Martin, K. H.; Zeiler, M. J.; Lian, E.; Avanzi, C.; Wiersma, C. J.; Nguyen, T. V.; Angala, B.; de Moura, V.; Jones, V.; Borlee, B. R.; Melander, C. and Jackson, M. "2-Aminoimidazoles Inhibit Mycobacterium Abscessus Biofilms in a Zinc-Dependent Manner" 2022 International Journal of Molecular Sciences, 23 (6), 2950. DOI: 10.3390/ijms23062950.
• Zeiler, M. J.; Connors, G. M.; Durling, G. M.; Oliver, A. G.; Marquez, L.; Melander, R. J.; Quave, C. L. and Melander, C. "Synthesis, Stereochemical Confirmation, and Derivatization of 12(S),16 Epsilon-Dihydroxycleroda-3,13-Dien-15,16-Olide, a Clerodane Diterpene that Sensitizes Methicillin-Resistant Staphylococcus Aureus to Beta-Lactam Antibiotics" 2022 Angewandte Chemie-International Edition, 61, e202117458. DOI: 10.1002/anie.202117458.
• Bailey, J.; Gallagher, L.; Barker, W. T.; Hubble, V. B.; Gasper, J.; Melander, C. and Manoil, C. "Genetic Dissection of Antibiotic Adjuvant Activity" 2022 Mbio, 13 (1), e03084-21. DOI: 10.1128/mbio.03084-21.
• Li, H. T.; Mattingly, A. E.; Jania, L. A.; Smith, R.; Melander, R. J.; Ernst, R. K.; Koller, B. H. and Melander, C. "Benzimidazole Isosteres of Salicylanilides are Highly Active Colistin Adjuvants" 2021 ACS Infectious Diseases, 7 (12), pp.3303-3313. DOI: 10.1021/acsinfecdis.1c00463.