The goals of our research are to discover or develop new classes of drugs that are effective in preventing infections by bacterial and viral pathogens. There is an especially pressing need for new classes of antibiotics that are effective toward drug-resistant bacterial strains, and our discovery program addresses this need.
Our lab carries out multifaceted studies of biologically active natural products, also known as secondary metabolites; designs peptide and protein inhibitors and probes of HIV-1 entry; and discovers and characterizes novel carbohydrate-binding proteins from understudied sources.
Natural products chemistry
We subscribe to the notion that as a result of millions of years of evolutionary pressure to effect specific biological processes, natural products represent an ideal starting point for identifying new inhibitors of macromolecular receptors and biological processes. Ongoing projects, approaches, and interests include isolation and complete structure elucidation of natural product inhibitors of mycobacterial enzymes and HIV-1 membrane fusion using multidimensional nuclear magnetic resonance (NMR) and modern spectroscopic techniques; determining the mechanism of action using bioassays and biophysical techniques; determining the structural basis accounting for activity by NMR methods; and for some cases, determining the structure-guided design and synthesis of natural product mimics or analogs.
Peptide and protein inhibitors of HIV-1 entry
A simplistic but generally accepted model for the initial step of HIV infection, or HIV-1 envelope-mediated membrane fusion, involves stepwise binding of the surface envelope glycoproteins, gp120/gp41, to cellular receptors, CD4 and CCR5 or CXCR4. Peptides and proteins derived from these receptors can block HIV-1 fusion, provide valuable mechanistic probes for studying fusion events, and elicit antibodies directed toward these molecules. Current projects include engineering stable trimeric gp41 N-helices as inhibitors and immunogens, chemical synthesis of post-translationally modified coreceptor-derived peptides and analogs, and high-resolution structural studies of each.
Novel carbohydrate-binding proteins
Protein-carbohydrate interactions play a critical role in countless biological processes and recognition events, including sperm-egg interactions leading to fertilization, leukocyte homing during the course of inflammation, and trafficking of tumor cells during metastasis. Alternatively, the vast majority of microorganisms and pathogens, if not all, display specific glycan structures, carbohydrate-binding proteins, or both on their cell or membrane surfaces.
Our efforts focus on the discovery of novel carbohydrate-binding proteins isolated from understudied sources, such as cyanobacteria and eubacteria, and comprehensive studies of carbohydrate specificity and recognition for these proteins. These efforts are accomplished through glycan profiling and biophysical techniques, evaluation of antimicrobial or antiviral activities, and high-resolution structure determination by NMR or x-ray crystallography.
Applying our Research
Infectious diseases take an enormous toll on human health. Our basic research endeavors seek to define the mechanisms by which pathogens cause infection and disease. These can, in turn, be used to develop new medicines for human health.
Need for Further Study
Unanswered questions in the field of antibiotic discovery and vaccine design include:
- How many new targets does a bacterium contain?
- Are these targets 'druggable'?
- What makes an antibiotic effective toward some strains and not others?