When administered in lethal levels, antibiotics trigger a fatal chain reaction within  bacteria that shreds the cell's DNA. But, when the level of antibiotic is less than lethal the same reaction causes DNA mutations that are not only survivable, but actually protect the bacteria from numerous antibiotics beyond the one it was exposed to, says a new study recently published in Molecular Cell. The findings underscore the potentially serious consequences to public health of administering antibiotics in low or incomplete doses.

"We know free radicals damage DNA, and when that happens, DNA repair systems get called into play that are known to introduce mistakes, or mutations," said Boston University Professor James J. Collins. "We arrived at the hypothesis that sub-lethal levels of antibiotics could bump up the mutation rate via the production of free radicals, and lead to the dramatic emergence of multi-drug resistance."

Testing their hypothesis on strains of E. coli and Staphylococcus,  researchers administered sub-lethal levels of five kinds of antibiotics and showed that each boosted levels of ROS and mutations in the bacterial DNA. They next conducted a series of experiments to show that bacteria initially subjected to a sub-lethal dose of one of the antibiotics exhibited cross-resistance to a number of the other antibiotics.

Finally, they sequenced the genes known to cause resistance to each antibiotic and pinpointed the mutations that protected the bacteria. Ironically, the researchers discovered that in some cases the bacteria were still be susceptible to the original antibiotic.

"The sub-lethal levels dramatically drove up the mutation levels, and produced a wide array of mutations," Collins observed. "Because you're not killing with the antibiotics, you're allowing many different types of mutants to survive. We discovered that in this zoo of mutants, you can actually have a mutant that could be killed by the antibiotic that produced the mutation but, as a result of its mutation, be resistant to other antibiotics."

 Administering low doses of antibiotics is common practice among farmers who apply low levels to livestock feed; doctors who prescribe them as placebos for people with viral infections; and patients who don't follow the full course of antibiotic treatment.

The study's findings may ultimately lead to the development of new antibiotic treatments enhanced with compounds designed to prevent the emergence of multi-drug resistance. For example, one potential treatment might inhibit the DNA damage repair systems that lead to the problematic mutations, while another might boost production of cell-destroying free radicals so that a low dose of antibiotic is sufficient to kill targeted bacterial cells.



Citation: Michael A. Kohanski, Mark A. DePristo, James J. Collins, 'Sublethal Antibiotic Treatment Leads to Multidrug Resistance via Radical-Induced Mutagenesis' Molecular Cell, Februaru 2010, 37(3), 311-320; doi: 10.1016/j.molcel.2010.01.003