Repressor lexA
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Repressor LexA or LexA is a repressor enzyme (EC 3.4.21.88) that represses SOS response genes coding for DNA polymerases required for repairing DNA damage. LexA is immobilized by action of RecA to which it binds. LexA proteolysis by a cleavage process is another process by which the repression action is impaired. LexA is intimately linked to RecA in the biochemical cycle of DNA damage and repair.
DNA damage can be inflicted by the action of antibiotics. Bacteria require topoisomerases such as DNA gyrase or topoisomerase IV for DNA replication. Antibiotics such as ciprofloxacin are able to prevent the action of these molecules by attaching themselves to the gyrase - DNA complex. This is counteracted by the polymerase repair molecules from the SOS response. Unfortunately the action is partly counterproductive because ciprofloxacin is also involved in the synthetic pathway to RecA type molecules which means that the bacteria responds to an antibiotic by starting to produce more repair molecules. What is more, the bacteria responds by producing mutated topoisomerases.
Mutations are traditionally thought of as happening as a random process and as a liability to the organism. Many strategies exist in a cell to curb the rate of mutations. Mutations on the other hand can also be part of a survival strategy. For the bacteria under attack from an antibiotic, mutations help to develop the right biochemistry needed for defence. It is found that certain polymerases in the SOS response to DNS damage actually are assigned the task of promoting mutations in the genes that code for the topoisomerases. As in evolution a larger variety of topoisomerases improve the survival chances.
In an experiment researchers in 2005 demonstrated that when LexA proteolysis was impaired in a special strain of E-coli, it was unable to build resistance to ciprofloxacin. This offers potential for combination therapy that combine quinolones with strategies aimed at interfering with the action of LexA.
[edit] References
- ^ Inhibition of Mutation and Combating the Evolution of Antibiotic Resistance Ryan T. Cirz, Jodie K. Chin, David R. Andes, Valérie de Crécy-Lagard, William A. Craig, Floyd E. Romesberg Plos Biology Volume 3, Issue 6, June 2005 Article open access publication
