With up to one-third of the world's population estimated to be infected with Mycobacterium tuberculosis (MTB), resistance to antibiotic treatments is a huge potential problem. A report in Cell by Clifton Barry, Valerie Mizrahi and colleagues now takes us a step closer to understanding how this resistance might arise.

While in its host, MTB encounters various adverse conditions that can damage its DNA. To generate strains that can survive under these conditions, the bacterium undergoes genetic mutation. But this can lead to antibiotic resistance if these mutations arise in genes such as rpoB , the mutation of which confers resistance to Rifampicin (Rif).

How do these mutations arise? One idea is that, in response to the attack mounted by human macrophages, the so-called 'SOS response' is activated. This pathway, which is regulated by the RecA protein, repairs the damaged DNA. But it is thought to do so using 'error-prone' DNA polymerases, which have a low rate of fidelity, so they introduce mutations as they complete the repair.

Helena Boshoff, a postdoctoral fellow, first confirmed that MTB has a damage-inducible mutagenesis system. She observed a 20–50-fold increase in Rif-resistant mutants when the bacteria were treated with a DNA-damaging agent (ultraviolet (UV) light).

Next, microarray analysis was used to identify which genes were induced in response to UV damage. Of the 158 candidates, only one — dnaE2 — encoded a known DNA polymerase. The authors therefore disrupted the dnaE2 gene in Mycobacterium, and showed that the observed resistance to Rif (and streptomycin) after UV irradiation was completely lost in these mutants. This resistance could be restored, however, by complementation with an extra copy of dnaE2.

To see whether DnaE2 might function as an error-prone polymerase, Boshoff looked at the types of mutations that arose in wild-type strains after UV treatment. She found that a high proportion (35.6%) had a double CC to TT transition, which is typical of the error-prone repair of a DNA lesion. By contrast, this characteristic mutation was not seen in the dnaE2-deficient strains. This is a surprising result, as enzymes of the family to which DnaE2 belongs were not thought to introduce errors while copying DNA.

So might DnaE2 be involved in drug resistance in vivo? To test this, the authors infected mice with wild-type, dnaE2-knockout or dnaE2-complemented knockout strains of MTB, irradiated them, then treated them with Rif. The result was clear — drug resistance emerged more frequently in the wild-type and complemented strains, than with the dnaE2 knockouts. And the implication is equally clear; DnaE2 is not only the main regulator of DNA-damage-induced mutagenesis in MTB, but it's also a new potential target for preventing the emergence of drug resistance in this pathogen.