*EPF506 04/18/2003
Text: New Research Shows Why Drugs Lose Punch Against Tuberculosis
(Finding is step forward in countering deadly drug-resistant TB) (1000)

Researchers from the National Institute for Allergy and Infectious Diseases (NIAID) announced April 17 that they have learned why once-reliable antibiotics are not working to cure tuberculosis and save patients' lives. The appearance of drug-resistant TB over the last 20 years has been a critical factor in the resurgence of the respiratory disease, once thought to have been overcome.

A press release says NIAID researcher Dr. Clifton E. Barry, working with associates in South Africa, discovered how mutations can occur in the DNA strand of the TB-causing bacteria. After mutations occur, formerly effective antibiotics no longer work against the bacteria. Multi-drug resistant TB can be cured, but only with much more intensive, expensive and long term treatment, a regimen that is unaffordable for many developing countries.

TB has resurged to become one of the world's most serious infectious diseases, claiming almost 2 million lives each year. Eight million people develop active cases of the disease each year; health officials estimate that one third of the world's population may be infected with the virus.

The insight from NIAID opens new avenues for scientists to explore in the development of drugs targeted specifically at multi-drug resistant TB, the release says.

The latest NIAID research is being reported in the journal Cell. The article is available online at http://www.sciencemag.org/sciencexpress/recent.shtml

Further information on the international campaign to overcome tuberculosis is available at http://www.stoptb.org/default.asp

The following terms is used in the text:

Polymerase: any of several enzymes that catalyze the formation of DNA or RNA

Following is the text of the NIAID press release:

(begin text)

National Institute of Allergy and Infectious Diseases
National Institutes of Health
Thursday, April 17, 2003

Sloppy Repair Helps TB Bug Resist Drugs

Shoddy work by a DNA-repair enzyme allows tuberculosis-causing bacteria to develop antibiotic resistance, scientists at the National Institute of Allergy and Infectious Diseases (NIAID) have discovered. Reported in the current issue of the journal Cell, the finding by Clifton E. Barry, III, Ph.D., and his colleagues in South Africa, could lead to new ways to treat TB without risking the development of drug resistance.

"Tuberculosis takes the lives of almost two million people each year, and eight million people develop active TB annually," says NIAID Director Anthony S. Fauci, M.D. "Especially alarming is the upsurge in cases of multidrug-resistant tuberculosis. A clearer understanding of how TB bacteria acquire drug resistance is essential if we are to control this disease," he adds.

Invading microbes, including the TB agent Mycobacterium tuberculosis (MTb), must withstand attacks by the host's immune system, adverse physical conditions, and, often, assaults by antibiotics and other drugs. Bacterial DNA damaged in the fray can be repaired by enzymes. Some bacterial DNA repair enzymes, though, are error-prone and often introduce mutations into the DNA strand. These mutations increase the odds of generating strains resistant to antibiotics.

During her research stints in both Dr. Barry's lab and the laboratory of Valerie Mizrahi, Ph.D., at the University of Witwatersrand in South Africa, co-author Helena Boshoff, Ph.D., worked to uncover details of MTb's DNA repair process. She used ultraviolet light to mimic the DNA damage suffered by MTb as it invades its host, and then she examined how MTb responded. Dr. Boshoff determined that MTb uses a DNA polymerase, DnaE2, to repair its DNA.

"We were surprised to find that MTb uses an enzyme from the major DNA polymerase replication family. In other organisms, including humans, such DNA polymerases are responsible for making perfect copies of DNA before the cell divides. Other DNA polymerases in this family are like straight-A students; they perform almost flawlessly. This is the first error-prone DNA polymerase from this family to be identified," says Dr. Barry.

MTb has two copies of the gene encoding DnaE enzyme. Previously, it was a mystery why the bacterium needed multiple copies of its DNA replication enzyme gene. With the realization that MTb relies on DnaE2 enzyme to introduce mutations into its DNA, thereby increasing the chance that drug resistance will result, this riddle is solved.

To learn what role the newly identified enzyme plays in animals, the researchers infected mice with either normal MTb or MTb lacking the DnaE2 gene. Mice infected with the normal MTb died quickly, while mice infected with the mutant germ contained the infection more successfully, indicating a role for DnaE2 in helping MTb persist in the host's cells. Finally, the researchers used mice to evaluate DnaE2's role in the evolution of drug resistance. Confirming findings from the test-tube experiments, mice infected with wild-type MTb developed resistance to a common antibiotic, while mice infected with strains lacking the gene-and hence, the error-prone repair enzyme-did not develop antibiotic resistance.

This new insight into the emergence of MTb drug resistance suggests ways to intervene with drugs targeted specifically at MTb's vital DNA repair enzyme. "For example," notes Dr. Barry, "therapies targeted at DnaE2 could block the development of drug resistance in people infected with drug-susceptible bacteria. Such a drug might also more efficiently clear non-replicating MTb."

NIAID is a component of the National Institutes of Health (NIH), which is an agency of the Department of Health and Human Services. NIAID supports basic and applied research to prevent, diagnose, and treat infectious and immune-mediated illnesses, including HIV/AIDS and other sexually transmitted diseases, illness from potential agents of bioterrorism, tuberculosis, malaria, autoimmune disorders, asthma and allergies.

Reference: R Seshadri et al. Complete genome sequence of the Q-fever pathogen, Coxiella burnetii . Proceedings of the National Academy of Sciences Online Early Edition the week of April 14, 2003. DOI 10.1073/pnas.0931379100.

The National Institute of Allergy and Infectious Diseases is a component of the National Institutes of Health, U.S. Department of Health and Human Services

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(Distributed by the Office of International Information Programs, U.S. Department of State. Web site: http://usinfo.state.gov)

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