In the continuing battle to counter growing antibiotic resistance, a new finding may help keep our current arsenal of antibacterial agents from having to be scrapped and replaced by an as yet unrealized new infection-fighting therapy.
By targeting an enzyme that bacteria use to swap genetic material, researchers at the University of North Carolina at Chapel Hill, have stopped the microbes' ability to spread, among other advantageous mutations, resistance to antibiotics.
"It turns out bacteria are very social," says Matthew Redinbo, a U.N.C. associate professor of chemistry, biochemistry and biophysics. "They pass genes between one another that keep one another intact." He adds that this transfer can occur between bacteria of either the same or different species.
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But as Redinbo and colleagues report in this week's Proceedings of the National Academy of Sciences USA, if the mechanism for this genetic transfer is blocked, the selective death of the antibiotic-resistant members of a bacterial culture is somehow triggered.
"We designed the whole thing to stop [the] transfer of genes," Redinbo says. "The biggest surprise was that stopping transfer also killed the resistant bacteria." He notes that his group does not know exactly how antibiotic resistant bacteria are killed off, but that interfering with the way a cell manipulates its DNA often causes cell death.
The DNA process disrupted by the U.N.C. team is called conjugation, which occurs when two bacteria sidle up to one another and punch holes in each of their outer membranes, allowing one microbe to shoot a single strand of DNA into the other. This mechanism is achieved via an enzyme called DNA relaxase, they noted, which acts as a gatekeeper, both initiating and ending the movement of the genetic material between the bacteria.
Scott Lujan, a graduate student in Redinbo's lab, made a key discovery: The DNA relaxase molecule has two "catalytic weapons" that allow it to perform its duties of breaking apart DNA strands. (Most other enzymes only have one; DNA relaxase needs two in order to contact the strands of DNA in the donating bacterial cell.) This finding alerted the team that in order for a chemical to disrupt DNA relaxase, it would need to block both catalytic sites on the enzyme.
They settled on bisphosphonates, which have already been approved by the Food and Drug Administration (FDA) to battle osteoporosis, a bone-thinning disease. Two drugs, clodronate and etidronate (aka Didronel), blocked DNA relaxase and, as a result, conjugation. An unexpected result of this disruption, however, was the fact that the antibiotic-resistant Escherichia coli bacteria that were trying to pass their genes along actually died when their DNA relaxase was shielded.
Redinbo says that his group is studying mice carrying infections in their gastrointestinal tract, skin and muscle tissue to see if the new mechanism for disrupting DNA relaxase is effective in the mammalian body. But he adds that "a clinician could use these approved drugs right away if faced with a resistant bacteria."