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.
