Jon Clardy, PhD
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School
Isolation and characterization of small molecule natural products; high-throughput screening for novel therapeutics
Discovering small molecule, natural products and their biology; high throughput screening for small molecule chemicals that interfere with microbial and mammalian cell processes.
Discovery and characterization of novel natural products that have potential therapeutic utility.
The large-scale screening of natural products for identifying novel medicinal compounds has gained traction in recent years as a bona fide approach for isolating new drugs against a range of maladies. These disorders would include gram negative bacterial infections, which are common in humans, and can lead to a variety of serious disorders. For example, the bacilli class of bacteria, which includes such well-known etiological agents as E. coli, Hemophilus influenzae, Salmonella, P. aeruginosa, and H. pylori, can cause chronic, as well as life-threatening, illnesses. Dr. Clardy’s microbial studies, linking chemistry and biology, continue to make important strides in deciphering the wide assortment of unidentified, small molecule, natural products.
The microbial studies also could yield insights into these molecules’ untapped potential as novel antibiotic therapeutics for gram negative bacteria. Because bacterial resistance to antibiotics is now a serious health issue, research that strives to break new ground in this area has enormous commercial potential. Moreover, Dr. Clardy’s extensive experience in isolating, identifying, and characterizing small molecule, natural products, has positioned his lab as an excellent partner for life science companies interested in this type of research.
Current Research Interests
Dr. Clardy’s lab employs several methods that combine genetics with chemical biology to characterize the structures and functions of microbial, small molecule, natural products. One of Dr. Clardy’s methods is the mining of the bioinformatic genome to discover cryptic metabolites and the genes that are responsible for their biosynthesis. This approach could uncover biologically active species with therapeutic properties, and could also yield insights into the chemical steps employed by the organism to produce these typically complex structures.
The lab is also interested in unearthing and characterizing new cryptic metabolites through investigations into the natural, stress-inducing perturbations that stimulate their production. This research is particularly important because artificial culture conditions might not provide the appropriate stimuli for triggering the gene expression of enzyme clusters required for the biosynthesis of these cellular metabolites. Therefore, mimicking the natural setting might be critical for uncovering novel, natural product, small molecules.
The lab is also studying chemical ecology, including the analysis of the complex interplay of certain symbiotic biological relationships and the chemical basis for these interactions.
Dr. Clardy canvasses the natural microbial world for previously unidentified, natural product, small molecules to annotate microbial biological pathways and to study interactions with macromolecules. These studies led to the development of high throughput screening assays that identify small molecule chemical antagonists of potential disease-related, molecular targets.
Dr. Clardy’s other area of interest is the impact of evolution on collective gene function. He recently published a study that explored this topic. There is a paucity of knowledge about the evolutionary process operating on gene clusters that encode biosynthetic products in a coordinated fashion. Dr. Clardy’s research on the Bacillus subtilis’ pksX gene cluster led to a breakthrough in structurally deciphering the end-product metabolite that is produced by the action of the bacillaene’s coordinated gene cluster. Employing genetics and structural techniques, the lab elucidated the complex structure of bacillaene. This work laid the foundation for future studies to address the sequential, enzymatic reactions that mediate the bacillaene’s biosynthesis, as well as its biological role.
Other experimental studies by Dr. Clardy have focused on the dauer development stage in C. elegans. The dauer stage enables the worm to subsist under harsh environmental conditions. The lab has performed extensive analyses on the dauer pheromone, and has discovered new structurally-related versions of this pheromone with different potencies.