Available Technology
Microbial VKOR as an anti-infective target
Technology:
Small molecule therapeutics for new class of antibiotics
Markets Addressed
Infections by multi-drug resistant gram-negative and gram-positive bacteria have become a significant medical problem. Prominent examples include the drug-resistant gram negative Pseudomonads (P. aeruginosa and Acinetobacter) and multi-drug resistant M. tuberculosis. These resistant infectious diseases are expanding at an alarming pace, yet the development of new antibiotics has been unable to provide tools to combat them.
Innovations and Advantages
Numerous labs have shown that many virulence factors are proteins stabilized by disulfide bonds. Thus, the enzymes involved in disulfide bond formation in bacteria are potential targets for new classes of antibiotics. Of considerable interest is Vitamin K epoxide reductase (VKOR) a necessary enzyme for vitamin K metabolism in humans and, subsequently, vitamin K-dependent blood coagulation. Inhibitors of the enzyme, namely warfarin and other coumarins have been used extensively to prevent thrombosis in humans. Prof. Beckwith and colleagues have discovered a completely different role for VKOR homologs in bacteria. The red-ox chemistry involved in vitamin K metabolism is used by bacteria to facilitate the formation of disulfide bonds, a key step in protein folding. Research has shown that M. tuberculosis is one pathogen that may need VKOR homologs for survival.
The invention comprises two aspects, small molecule inhibitors of Mycobacterium VKOR and a screen against DsbA and DsbB, conserved VKOR homologs in a variety of gram-negative and gram-positive pathogens. Initial screening has identified over 20 candidates for development as potential antibiotics, particularly for the treatment on M. tuberculosis. In addition, the Beckwith lab has developed a high-throughput screening against bacterial VKOR, DsbA, and DsbB; with a consequent cross-screen against human VKOR. Plans to screen internally are developing.
Additional Information
Intellectual Property Status: A patent application covering both methods of screening and compositions of matter have been filed and is available for worldwide licensing on an exclusive or non-exclusive basis.
Tweet
Inventor(s):
Beckwith, Jonathan R.
Berkmen, Mehmet
Boyd, Dana H.
Dutton, Rachel J.
Categories:
For further information, please contact:
Michal Preminger, Director of Business Development
(617) 432-0920
Reference Harvard Case #3272