20 May 2005
Halting Evolution To Fight Illness
by Kate Melville
Researchers at The Scripps Research Institute and the University of Wisconsin, writing in the journal PloS Biology, describe how E. coli evolution could be halted in its tracks by subjecting the bacteria to compounds that block a protein called LexA. LexA promotes mutations and helps the pathogen evolve resistance to antibiotics. Interfering with this protein renders the bacteria unable to evolve resistance to common antibiotics. "If you inhibit this pathway, the bacteria cannot evolve," says study leader Floyd Romesberg, from Scripps. Since the evolution of resistance is under the control of LexA, compounds that block the protein might prolong the potency of existing antibiotics.
Romesberg said that mutation was a programmed stress response. If a cell senses damage, and if the damage persists beyond its ability to repair it, the cell will turn on its mutation machinery and open the floodgates for evolution. When E. coli cells are subjected to damage, they upregulate repair enzymes, which then go to work trying to fix the problem. If the damage persists, the cell upregulates recombination enzymes, which are tasked with recombining the DNA - another way to repair it. And, says Romesberg, if the damage still persists, the cells upregulate enzymes whose sole task is to make mutations. Inducing mutations is an effective evolutionary strategy for dealing with environmental changes that maximize the chances that a progeny cell will be better adapted. Romesberg reasoned that since mutations can be turned on full-force, perhaps they could be shut off as well. Doing so, he says, would put a halt to evolution - an interesting prospect because the mutations responsible for evolution are the underlying causes of cancer and aging as well. "Evolution is not an unstoppable force," says Romesberg. "There is a biochemistry underlying it and it is subject to intervention."
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.
Romesberg's work could have profound implications in the battle against antibiotic resistance which is a major health problem in the United States. Multiple drug-resistant TB is no longer susceptible to broad categories of antibiotics, such as rifampicin, isoniazid, and streptomycin. Some strains of the common hospital infection-causing bacteria Staphylococcus aureus are resistant to all antibiotics except vancomycin, which is a drug of last resort, and some strains of Streptococcus pneumoniae are even resistant to vancomycin. Certain strains of Shigella dysenteriae, the cause of epidemic dysentery, have even become resistant to all but a single drug - the quinolone ciprofloxacin - and may soon become completely untreatable.
Romesberg's work is also significant for cancer research as cancer cells mutate readily and often acquire resistance to common chemotherapies. If researchers can identify the molecules that human cancer cells use to drive evolution, they can perhaps find ways of intervening and preventing the evolution of chemotherapy resistance in those cancer cells.