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Biological Chemistry

Disabling Resistance

Inhibiting key protease prevents bacteria from evolving drug resistance

May 16, 2005 | A version of this story appeared in Volume 83, Issue 20

Romesberg (left) and grad student Ryan T. Cirz are part of the team that showed how to stop bacteria from evolving resistance.
Romesberg (left) and grad student Ryan T. Cirz are part of the team that showed how to stop bacteria from evolving resistance.

Many antibiotics are rendered ineffective because bacteria become resistant to them. Now, a new study uncovers a potential therapeutic target for small-molecule drugs--a protease called LexA--that could stop bacteria from evolving resistance to antibiotics such as ciprofloxacin and rifampicin (PLoS Biol., published online May 10, pbio.0030176).

Drug resistance has been considered an inescapable outcome of mutations during genomic replication. It turns out, however, that spontaneous mutations aren't the main way that bacteria acquire resistance to ciprofloxacin.

Many people think that mutations are primarily due to mistakes during DNA replication despite the high fidelity of the process, but that's only a relatively minor route to mutations, says lead author Floyd E. Romesberg, assistant professor of chemistry at Scripps Research Institute. "Those rates are just too slow to be able to generate the number of mutations required for resistance."

In response to the stressful conditions created by antibiotics, bacteria instead turn to another mutation mechanism--part of the so-called SOS damage response--that is 10,000 times faster than normal genomic mutations. This system is usually turned on in response to DNA damage. Because quinolones such as ciprofloxacin work by interfering with enzymes that control the topology of DNA, they lead to DNA damage and may actually trigger the evolution of resistance.

The protease LexA is the gatekeeper of this alternative mutation pathway. As long as LexA remains intact, it represses the production of three DNA polymerases that are nonessential for genomic replication but required for mutations in response to DNA damage. Cleaving LexA allows those proteins to be produced and mutations to happen. Blocking LexA cleavage renders the bacteria unable to evolve resistance, making LexA a potential target for a small-molecule drug that could be administered in combination with the an tibiotic.

To test whether LexA is essential for mutations through SOS damage response, Romesberg and coworkers at Scripps and the University of Wisconsin Medical School, Madison, used a strain of Escherichia coli that couldn't cleave LexA. They grew the strain at antibiotic concentrations barely higher than the minimum necessary to work. If the strain could mutate, this condition made it as easy as possible to do so, Romesberg says. They found that the bacteria were not able to evolve resistance to ciprofloxacin or rifampicin, either in cell cultures or in a mouse model.

Disabling LexA "will be a highly novel approach to incapacitating bacteria to cope with the challenge of antibiotics. However, it is hard to predict what the consequence of such interference will be," says Shahriar Mobashery, a chemistry professor at the University of Notre Dame who studies bacterial resistance. "It will be interesting to see how this knowledge will be exploited in prolonging the usefulness of existing classes of antibiotics."

So far, the approach has been shown to work with antibiotics that directly damage DNA. "Even if it were only applicable to those drugs that directly damage DNA, it still hits the major market of antibiotics," Romesberg says. "If that were the case, I'm sort of okay with that." His group is now working to determine whether interfering with LexA also prevents bacteria from evolving resistance to other classes of antibiotics.


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