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Doctors insist that patients take a full course of antibiotics to prevent drug resistance, which bacteria can develop when the dose is too low. A study now shows that inadequate doses can elicit resistance not only to administered antibiotics but to other antibiotics as well. And the study points to DNA damage and error-prone DNA repair as the cause.

The work could help scientists develop new strategies to fight the growing problem of antibiotic resistance. According to the Centers for Disease Control & Prevention, “The number of bacteria resistant to antibiotics has increased in the last decade.”

Biomedical engineering professor James J. Collins and coworkers at Boston University have found that resistance can develop when drug-induced radical oxygen species damage bacterial DNA. Although the DNA repair system often fixes the DNA damage, it is error-prone and can generate random mutations that affect bacterial resistance, the study finds (Mol. Cell, DOI: 10.1016/j.molcel.2010.01.003).

Resistance might or might not develop against the administered agent. For example, low-dose ampicillin might elicit mutant bacteria with broad resistance to other antibiotics but not to ampicillin itself. Models of low-dose-antibiotic resistance have generally focused on resistance to administered agents, not to other drugs.

“These findings drive home the need for tighter regulations on the use of antibiotics, especially in agriculture; for doctors to be more disciplined in their prescription of antibiotics; and for patients to be more disciplined in following their prescriptions,” Collins says. Co-administration of DNA repair system inhibitors—to prevent DNA repair errors that cause mutations—might help address the problem, he notes.

The results suggest “that any bactericidal drug in a therapeutic cocktail may assist bacteria in attaining resistance to the entire combination,” write infectious disease specialist Deborah T. Hung of the Broad Institute, in Cambridge, Mass., and coworker Benjamin B. Kaufmann in a commentary about the work. The findings “remind us how little we know about how resistance is generated at the molecular level and underscore why preventing the emergence of these lethal strains remains such a formidable challenge.”