Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

To stop evolution: New way of fighting antibiotic resistance demonstrated by Scripps scientists

19.05.2005


A team of scientists at The Scripps Research Institute and the University of Wisconsin have demonstrated a new way of fighting antibiotic resistance: by stopping evolution.



In the June issue of the open-access journal PloS Biology, the team describes how a protein called LexA in the bacterium Escherichia coli promotes mutations and helps the pathogen evolve resistance to antibiotics. The scientists also show that E. coli evolution could be halted in its tracks by subjecting the bacteria to compounds that block LexA. Interfering with this protein renders the bacteria unable to evolve resistance to the common antibiotics ciprofloxacin and rifampicin. "If you inhibit this pathway, the bacteria cannot evolve," says Scripps Research Assistant Professor Floyd Romesberg, Ph.D., who led the study.

Since the evolution of resistance is under the control of LexA, compounds that block the protein might prolong the potency of existing antibiotics.


Evolution -- Its not Like Death and Taxes Anymore

This research raises fundamental questions about evolution. Biologists have often thought about evolution in the same way many think about death and taxes -- something inevitable. But Romesberg is a chemist, and he found himself asking not only how, but why evolution happens.

For the last few years, Romesberg has led an effort to understand the genes that drive evolution, an innovative way of thinking because scientists have more often understood evolution as the force that drives genes. What underlies evolution is mutation -- changes in the DNA. "Mutations are the fuel for evolution," says Romesberg.

Because of the potential harm of mutations, humans and other mammals have evolved to make as few as possible. The machinery inside our cells has the ability to replicate our genomes extremely well, and the "polymerase" enzymes that replicate our DNA rarely make mistakes. Even when they do, we have multiple, redundant repair and proofreading mechanisms that would make even the most six-sigma-compliant NASA engineer jealous.

Nevertheless, all organisms are prone to some level of damage because no replication machinery is perfect, and with large genomes of billions of bases of DNA to be copied many billions of times over the lifetime of an organism, a certain level of spontaneous mutations will occur -- mistakes that escape repair and become part of the DNA of the cell in which they occur. Scientists have generally thought that slowly over time, these mutations accumulate and species diverge.

However, Romesberg and his colleagues believe that cells are not just the passive victims of random mutations, but have ways of initiating mutations in their own DNA. Evidence for this includes the fact that the rates of mutation in some cells does not seem consistent with the mutation rates associated with DNA replication.

Some cells, like bacteria subjected to antibiotics, seem to acquire mutations at a much higher rate. Romesberg reasons that these rapid mutations may sometimes be part of a mechanism organisms have to rapidly evolve when they need to.

Stress and Mutations

A few years ago, when he was first starting to think about this, Romesberg encountered a paper in a scientific journal that discussed certain genes that "make mutations," as he put it. When these genes are deleted from cells, the cells lose their ability to mutate, even when subjected to massive amounts of ultraviolet light.

This brought Romesberg to the conclusion that mutation is a programmed stress response -- a survival mechanism. If the 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.

Take the bacterium Escherichia coli for instance. 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.

Presumably, inducing mutations is an effective evolutionary strategy for dealing with environmental changes that maximize the chances that a progeny cell will be better adapted. In order to evolve, organisms have to mutate, so they turn on the mutation process when they are threatened with extinction.

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."

The Scourge of Antibiotic Resistance

One thing that scientists would like to change about bacteria and cancer cells is their changeability.

At the dawn of the 20th century, bacterial infections accounted for several of the leading causes of death in the United States. But then came the antibiotic revolution. Antibiotic "wonder drugs" toppled tuberculosis (TB) and typhoid fever, controlled cholera and gonorrhea, reduced staphylococcal dysentery, and lowered the incidence of many other pandemic bacterial infections. These antibiotics are basically natural chemicals (or derivatives of natural chemicals) produced by other bacteria or fungi in the environment to kill off the competition. Scientists in the last century have discovered a number of these natural "antibiotic" products and have used them as the basis for treating bacterial infections.

By the middle of the century, the threat posed by many types of bacteria seemed to be waning. Bacterial infections that once topped the list as leading causes of death in the United States were no longer among the top ten. The average life expectancy in the United States soared from 47.3 years in 1900 to almost 80 years today, and antibiotics are partly to thank for this.

But in the last few decades, mutant strains of several types of bacteria with the ability to resist antibiotics have emerged, including those that cause TB, pneumonia, cholera, typhoid, salmonella, and staphylococcal dysentery. These diseases are coming back resistant to the antibiotics that have been used to treat them, and people infected with these resistant strains have to be treated with alternative antibiotics. For years scientists have been combating drug resistance by coming up with new types of antibiotics, and for years bacteria have been evolving ways around these antibiotics.

Antibiotic resistance is a major health problem in the United States. According to the U.S. Food and Drug Administration (FDA), about 70 percent of bacteria that cause infections in hospitals are resistant to at least one antibiotic, and some are so resistant that no antibiotics are effective, and they must be treated with experimental and potentially toxic drugs.

Now some super bugs -- multiple drug-resistant bacteria -- are emerging as an even greater threat. 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. This is a major concern for public health because, according to the World Health Organization (WHO), large-scale epidemics of dysentery driven by this pathogen have been known to cause tens of thousands of deaths in Central America, South Asia, and central and southern Africa.

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 experiments, the rodents were given rifampicin or ciprofloxin, and the scientists found that nearly all the wild-type E. coli cells had grown fully resistant to the antibiotics after three days.

This research is also significant for cancer because cancer cells mutate readily and often acquire resistance to common chemotherapies. Romesberg hopes that if he and his colleagues can identify the molecules that human cancer cells use to drive evolution, they can find ways of intervening and preventing the evolution of chemotherapy resistance in these cancer cells. Last year Romesberg was awarded a Department of Defense Breast Cancer Research Program Idea Award of $563,100 to identify the genes in Saccharomyces cerevisiae yeast and human cells that induce mutations that can transform normal cells into cancer cells.

Jason Bardi | EurekAlert!
Further information:
http://www.scripps.edu

More articles from Life Sciences:

nachricht Unique genome architectures after fertilisation in single-cell embryos
30.03.2017 | IMBA - Institut für Molekulare Biotechnologie der Österreichischen Akademie der Wissenschaften GmbH

nachricht Transport of molecular motors into cilia
28.03.2017 | Aarhus University

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: A Challenging European Research Project to Develop New Tiny Microscopes

The Institute of Semiconductor Technology and the Institute of Physical and Theoretical Chemistry, both members of the Laboratory for Emerging Nanometrology (LENA), at Technische Universität Braunschweig are partners in a new European research project entitled ChipScope, which aims to develop a completely new and extremely small optical microscope capable of observing the interior of living cells in real time. A consortium of 7 partners from 5 countries will tackle this issue with very ambitious objectives during a four-year research program.

To demonstrate the usefulness of this new scientific tool, at the end of the project the developed chip-sized microscope will be used to observe in real-time...

Im Focus: Giant Magnetic Fields in the Universe

Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.

The results will be published on March 22 in the journal „Astronomy & Astrophysics“.

Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...

Im Focus: Tracing down linear ubiquitination

Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.

Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...

Im Focus: Perovskite edges can be tuned for optoelectronic performance

Layered 2D material improves efficiency for solar cells and LEDs

In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...

Im Focus: Polymer-coated silicon nanosheets as alternative to graphene: A perfect team for nanoelectronics

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

International Land Use Symposium ILUS 2017: Call for Abstracts and Registration open

20.03.2017 | Event News

CONNECT 2017: International congress on connective tissue

14.03.2017 | Event News

ICTM Conference: Turbine Construction between Big Data and Additive Manufacturing

07.03.2017 | Event News

 
Latest News

'On-off switch' brings researchers a step closer to potential HIV vaccine

30.03.2017 | Health and Medicine

Penn studies find promise for innovations in liquid biopsies

30.03.2017 | Health and Medicine

An LED-based device for imaging radiation induced skin damage

30.03.2017 | Medical Engineering

VideoLinks
B2B-VideoLinks
More VideoLinks >>>