Method for selecting inhibitors of Rm1A
L-rhamnose is a 6-deoxyhexose that is found on the cell wall of many pathogenic microorganisms, however it is absent from mammals. In Gram-negative bacteria L-rhamnose is one of the important residues of the O-antigen of lipopolysaccharide, a factor which is a key determinant for the virulence of these species. Gram-positive bacteria such as streptococci and mycobacteria utilise L-rhamnose in the arabinogalactan (AG) that attaches the lipid mycolic acid layer to the peptidoglycan layer which is of vital importance to mycobacteria.
Four enzymes; RmlA, RmlB, RmlC and RmlD are required for the synthesis of L-rhamnose. Significantly, these proteins are highly conserved amongst microorganisms and therefore conclusions drawn from the structure of a protein from one species will have strong implications for the corresponding enzyme of another origin.
As RmlA catalyses the first of four steps resulting in the synthesis of L-rhamnose, it is an attractive target in the development of novel antibiotics.
Key Benefits
- Our invention provides a purified and crystallised form of RmlA and its X-ray structure. In addition, it also provides a method of selecting agents which inhibit the enzyme RmlA, such as,
- providing a model of the active or regulatory site (s) of RmlA;
- reviewing the structure of a potential inhibitory agent for at least one of these sites;
- analysing the potential interaction of said agent in said site (s).
Applications
- This technology may prove to be of substantial benefit to pharmaceutical and biotechnology companies, to select for anti-microbial compounds for further development. For example, an anti-bacterial or anti-fungal agent which binds to an active or regulatory site of RmlA sufficiently tightly to impede the biosynthesis of rhamnose and thus growth of the micro-organism.
IP Status
The University of St. Andrews has applied for a European Patent (Application No. 01949689.2) and has applied for International patent protection (Canadian Patent Application No. 2416064, US Patent Application No. 10/332935). As yet, there are no commercial parties involved. The University would welcome enquiries from commercial parties interested in entering into a licensing arrangement.
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University of St Andrews, Knowledge Transfer Centre,
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