For some time now, bacterial drug resistance has been considered a consequence of errors (called mutations) that accumulate spontaneously during replication of the bacterial genome. In many cases those mutations are either inconsequential or harmful to the bacteria, but on rare occasions, they provide an accidental benefit: resistance to the drugs that kill them. Because the mutations were assumed to be spontaneous, there seemed no obvious way to prevent them and thus antibiotic resistance appeared inevitable. However, in their work published in the open-access journal PLoS Biology, a collaborative group led by Floyd Romesberg has uncovered evidence that spontaneous mutations are not the only way in which bacteria acquire resistance to antibiotics; the bacteria, rather than passively waiting around for a lucky break, may play an active role in their own evolution.

DNA damage, induced by certain antibiotics (prominently those of the quinolone class) or other stressors, sets off a bacterium's emergency repair mechanism: the SOS DNA damage response. Under normal conditions, the genes are turned off by a special repressor protein called LexA, but in response to the damaged DNA, the LexA repressor is cleaved and no longer inhibits transcription of the SOS response genes. Romesberg's group proposes that antibiotic-mediated DNA damage generates a reduction in the concentration of LexA that is sufficient to increase the expression of three nonessential DNA polymerases that promote DNA repair and cause mutations in bacterial DNA that can lead to antibiotic resistance.

This suggests that quinolone antibiotics (and other antibiotics that cause similar kinds of DNA damage) may increase the likelihood that bacteria will evolve resistance. However, some hope remains: the researchers also demonstrated that blocking LexA cleavage prevents mutation and results in bacteria that are unable to evolve antibiotic resistance. Thus, developing novel therapeutic
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Contact: Paul Ocampo
press@plos.org
415-624-1224
Public Library of Science
9-May-2005

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