Health and Synthetic Biology – III
Translation by A. Martínez
Vaccines and drugs
Discovering new drugs
The reconfiguration of genetic circuits enables an organism to respond to new types of physical or chemical stimuli, expressing reporter genes –such as fluorescent proteins or antibiotic resistance factors-. This turns out to be of special interest to the discovery of new interactions between potential drugs and the substances within the cell.
|FromWebber, et al., (2009)|
One exampleis the work of Webber and collaborators, who managed to identify a molecule that sensitizes Mycobacterium tuberculosis to an antibiotic. The researchers used a synthetic system in mammalian cells that were able to detect the interaction between the operator OethR –an operator is the part of a promoter to which transcription factors are binded- and the protein EthR, both elements from M. tuberculosis.
Naturally, M. tuberculosis protein EthR binds to the operator OethR and represses the transcription of another protein, EthA, which activates the prodrug ethionamide; therefore, the repressive effect of EthR is involved with the resistance of M. tuberculosis to this kind of drug, which is generally used as a last line treatment.
|From CHEMICAL REGISTER|
The synthetic circuit generated by the researchers consists on a domain from the protein EthR and a domain from Herpes simplex's VP16 protein. When the operator OethR was placed inside a synthetic promoter responsible for regulating a reporter gene’s transcription –which, in this case, was the human fetal alkaline phosphatase, or SEAP- it was observed that the chimeric factor EthR-VP16 induced the expression of the reporter SEAP.
The researchers came to hypothesize that a molecule capable of binding to EthR could also break the interaction with the operator OethR and would decrease the expression of SEAP.
When the researchers exposed the HEK-293 cells, containing the synthetic circuit, to a library of chemical compounds, they detected that the presence of a 2-phenyl-ethyl-butyratemolecule –a strawberry flavor food additive- was related to the decreased expression of SEAP.
After excluding cytotoxicity as a cause of the decrease in SEAP, and after the circuit had been validated in a prokaryotic model, Webber and collaborators proved that 2-phenyl-ethyl-butyrate increases the vulnerability of the M. tuberculosis cells against the exposure to ethionamide. In principle, this approach may be also applied to sensitize other microorganisms to antibiotics.