Treating multiple drug-resistant bacterial infections can be a hundred times more expensive than treating normal infections, and the WHO estimates the total cost of treating all hospital-borne antibiotic resistant bacterial infections is around $10 billion a year. Worse, with modern rapid transit and world travel, multiple drug-resistant bacteria could potentially spread beyond the isolated confines of a hospital and into the general population.
If one could design drugs to halt the enzymes that make mutations in bacteria, this could be a way of combating the evolution of antibiotic resistance.
The Dramatic Effect of LexA Inhibition
Halting evolution is exactly what Romesberg and his colleagues demonstrated in their latest PloS paper. They showed that when E. coli cells were treated with the antibiotics ciprofloxacin and rifampicin, they turned on their mutation pathways and rapidly evolved resistance to the antibiotics. Wanting to find the proteins that turn on the mutations, Romesberg and his colleagues identified a master regulatory switch that, if inhibited, blocks the ability of the cells to mutate.
This was the protein LexA, which belongs to the class of signaling enzymes known as serine proteases and works by cutting the amino acid chain of other proteins. Romesberg and his colleagues showed that LexA's action was necessary for the evolution of resistance to the antibiotics in vitro.
The effect in vivo was dramatic. Blocking LexA in rodent models of E. coli infections halted the growth of antibiotic resistance. Three days after being subjected to antibiotics, the rodents showed no level of resistance to rifampicin or ciprofloxin, when they harbored a variant of LexA that was catalytically inactive. In control
Source:Scripps Research Institute