Scientists at the National Institute of Allergy and Infectious Diseases (NIAID) have discovered that shoddy work by a DNA-repair enzyme allows tuberculosis-causing bacteria to develop antibiotic resistance. The finding by Clifton E. Barry, III, 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, "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.

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."