- Repressor lexA
Repressor LexA or LexA is a
repressor enzyme (EC number|3.4.21.88) that repressesSOS response gene s coding forDNA polymerase s required for repairing DNA damage. LexA is intimately linked toRecA in the biochemical cycle of DNA damage and repair. RecA binds to DNA-bound LexA causing LexA to cleave itself in a process called autoproteolysis.DNA damage can be inflicted by the action of antibiotics. Bacteria require
topoisomerase s such asDNA gyrase ortopoisomerase IV forDNA replication . Antibiotics such asciprofloxacin 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 theSOS response . Unfortunately the action is partly counterproductive becauseciprofloxacin is also involved in the synthetic pathway toRecA type molecules which means that the bacteria responds to an antibiotic by starting to produce more repair proteins. These repair proteins can lead to eventual benevolent mutations which can render the bacteria resistant to ciprofloxacin.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 defense. Certain polymerases in the SOS pathway are error-prone in their copying of DNA which leads to mutations. While these mutations are often lethal to the cell, they can also lead to mutations which improve the bacteria's survival. In the specific case of topoisomerases, some bacteria have mutated one of their amino acids so that the ciproflaxin can only create a weak bond to the topoisomerase. This is one of the methods that bacteria use to become resistant to antibiotics.
Impaired LexA proteolysis has been shown to interfere with
ciprofloxacin resistance. [cite journal |author=Cirz RT, Chin JK, Andes DR, "et al" |title=Inhibition of mutation and combating the evolution of antibiotic resistance |journal=PLoS Biol. |volume=3 |issue=6 |pages=e176 |year=2005 |pmid=15869329 |doi=10.1371/journal.pbio.0030176 | url = http://biology.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pbio.0030176] This offers potential forcombination therapy that combinequinolone s with strategies aimed at interfering with the action of LexA either directly, or via RecA.References
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