Common meds halt mutations in bacteria

Antibiotic-resistant bacteria have become a global health threat, but new research gives a clue to targeting the evolution of one particular microbial species and potentially stopping a pernicious – and growing – problem.

In a study published in the journal Molecular Cell, researchers show that bacterial mutations leading to antibiotic resistance can be prevented with already developed drugs – potentially a more effective strategy than designing ever-stronger medications.

“We wanted to understand the molecular mechanism underlying the evolutionary arms race that pathogenic bacteria wage against our immune systems, and against antibiotics,” says senior author Susan Rosenberg of Baylor College of Medicine, Houston, US. 

“This is motivated by the hope of being able to make or identify a fundamentally new kind of drug to slow bacterial evolution.”

Rosenberg and colleagues began by studying how Escherichia coli fights against ciprofloxacin, a common quinolone antibiotic.

They found that in 10% to 25% of exposed E. coli cells, ciprofloxacin triggered a stress response, marked by a high level of reactive oxygen species (ROS).

ROS stress response deteriorates cell DNA, which the affected bacteria then tries to repair. The researchers say that some of the cells, which they call “gamblers”, take a more haphazard approach to trying to repair themselves, using an “error-prone” process that leads to genetic mutations.

Not all the mutations work, of course. Some cells just die. But some lucky ones find a mutation that repairs the DNA and makes them resistant to the antibiotic.

“This particular mechanism is likely to be important for resistance to quinolones – very widely used antibiotics for which clinical resistance is common and occurs by new mutations in the clinic,” Rosenberg says.

“It is likely also to illuminate formation of resistance to other antibiotics, in which the main route to resistance is new mutations, as opposed to those antibiotics for which the main route is acquisition of resistance genes from other bacteria.”

The next question is: How can scientists prevent bacteria from going through this mutation process?

In fact, there are already drugs on the market that inhibit ROS response, because the reaction is also harmful in human cells. In follow-up experiments, Rosenberg and colleagues found that pairing antibiotics with the ROS-inhibitor drug edaravone, commonly used in stroke treatment, inhibits ROS spikes in the E. coli cells.

Correspondingly, the ciprofloxacin-induced mutations that can lead to antibiotic resistance were also stymied.

The team suggests that pairing antibiotics with ROS inhibitors could prevent bacteria from mutating into antibiotic-resistant strains.

“These data serve as a proof-of-concept for small-molecule inhibitors that could be administered with antibiotics to reduce resistance evolution by impeding differentiation of gamblers, without harming antibiotic activity,” Rosenberg says.

She points out that because ROS-inhibitor drugs such as edaravone are already approved for human safety by the US Food and Drug Administration, human trials could be fast-tracked.

“Drugs like this could be used with standard antibiotics to slow evolution of resistance,” she says.

“These could potentially extend the use of current antibiotics, and possibly work as mono-therapies by tilting the evolutionary battle in favour of the immune system.”