David Crich, D.ès Sc.
Medicinal, Synthetic and Carbohydrate Chemistry
The University of Georgia
Recruited: 2019
David Crich is an internationally acclaimed organic chemist with major contributions in the fields of mechanistic and synthetic organic chemistry, medicinal chemistry and glycochemistry. Chemistry is key to glycoscience, the study of sugars and carbohydrates, which is revolutionizing the field of biology. Crich and his team have spent more than 20 years solving important problems in carbohydrate chemistry – and advancing glycoscience as a whole.
Crich and his team are particularly focused on making hard-to-access sugar structures, or oligosaccharides, available to other researchers for use as diagnostic tools and therapeutic agents. By combining their expertise in carbohydrate reaction mechanisms with development of improved chemical processes, Crich’s team innovated ways to synthesize these sugar structures in the lab. Specifically, they found simple and practical methods for synthesizing specific types of glycosidic bonds. (A glycosidic bond is the link that connects a sugar molecule to another molecule, enabling the formation of complex sugar structures.)
Some of the Crich team’s biggest successes include their pioneering of ways to synthesize the β-mannopyranosides and the α-sialosides, two types of glycosidic bond that are each found in a number of important oligosaccharides. Before Crich’s work, constructing these bonds was considered one of carbohydrate chemistry’s biggest challenges. But the methods developed in the Crich lab have made this kind of synthesis simple to the point of being routine.
The Crich lab has continued to build on that research. The group is currently focused on legionaminic and pseudaminic acids, which are found only in bacteria. Like the team’s breakthrough with β-mannopyranosides, the methods they are developing will enable many other scientists to study the corresponding sugar structures more efficiently and effectively, fueling research into antibiotics and antibacterial vaccines.
In parallel, drawing on his experience in carbohydrate chemistry, Crich is now tackling one of medicine’s most pressing and urgent challenges: defeating drug-resistant bacteria, particularly those known as the ESKAPE pathogens. The pathogens are six infectious diseases that have developed resistance to commonly used antibiotics and are the leading cause of hospital-acquired infections.
Working with a class of antibiotics called aminoglycosides, Crich and his team — together with collaborators in Zurich — are developing new therapeutic agents to defeat ESKAPE pathogens. Aminoglycosides are powerful drugs, but they have been prescribed less in recent years because bacteria like the ESKAPE pathogens have grown more resistant to them. Aminoglycosides can also cause side effects such as ototoxicity, drug-induced damage to the ear that can result in balance problems and hearing loss.
Building on existing aminoglycosides, Crich’s team is designing synthetic compounds with the same potent bacteria-fighting properties as currently available antibiotics, while also sidestepping the resistance mechanisms of the ESKAPE pathogens, and reducing the toxic side effects of conventional aminoglycosides.
Crich’s newly designed compounds, crafted through synthetic chemistry, have their foundation in existing natural aminoglycosides. One such natural product, apramycin, is an aminoglycoside antibiotic that eludes ESKAPE resistance and is less toxic than the compounds currently in clinical use. Alongside the program to develop improved synthetic drugs, Crich and his colleagues in Zurich are developing apramycin for use in human patients through a Swiss biotech start-up, Juvabis. Crich aims to apply this entrepreneurial experience in Georgia to launch new biotech companies here.
Crich and his team also currently apply their talents in the area of glycomimetics and in other areas of medicinal chemistry. Glycomimetics are compounds that mimic the structures of natural carbohydrates, yet are tweaked so they work better as therapeutics.
One type of glycomimetics that Crich is exploring are synthetic versions of β-(1→3)-glucans. The natural versions of these are commonly used as dietary supplements that boost the immune system. These substances are found in mushrooms and algae, but it’s difficult to obtain pure and consistent samples from these natural sources. Crich hopes that a synthetic version – a lab-crafted substance that models the same effects – could have improved properties, making it ideal for use as a research tool or a therapeutic treatment.
Finally, in other areas of medicinal chemistry the Crich lab studies unusual, underexplored chemical groups. Because drug developers tend to focus on the most commonly and widely studied chemical groups, this work is essential to expanding diversity and creating new opportunities for drug design.
Research
- Developing novel anti-infective agents to treat multi-drug-resistant infectious diseases
- Developing new aminoglycoside antibiotics to treat ESKAPE pathogens with reduced toxicity
- Design, synthesis and evaluation of glycomimetics to be used as novel therapeutic agents
- Synthesis of glycosidic bonds with an emphasis on bacterial sialic acids, legionaminic and pseudaminic acid
- Developing and exploiting underrepresented functional groups in medicinal chemistry and drug design
Straight from the Scholar
“At the University of Georgia, with labs in the Pharmaceutical and Biomedical Sciences Department and in the Complex Carbohydrate Research Center, and a joint appointment in the Chemistry Department, I have access to world class colleagues in the biomedical and glycosciences as well as to outstanding facilities all within arm’s reach. I look forward developing our current programs further and to developing more collaborations within the biomedical sciences at UGA and elsewhere in Georgia, so as to contribute our expertise to the solution of significant biomedical problems.”
