Anti-Evolving Drugs May Slow Antibiotic Resistance in Bacteria – ScienceDaily


The failure of existing antibiotics to fight infections is a major health threat worldwide. While the traditional strategy to combat drug resistance has been to develop new antibiotics, a more sustainable long-term approach may be preventing bacteria from developing it in the first place. So far, a major obstacle to this approach is that it has not been clear how antibiotics induce new mutations.

In a study published on April 1 in the journal Molecular CellResearchers have discovered that a mechanism by which antibiotics induce drug resistance mutations in bacteria is triggering the generation of high levels of toxic molecules called reactive oxygen species (ROS). Additionally, treatment with a ROS-lowering drug approved by the U.S. Food and Drug Administration for other purposes prevented these antibiotic-induced mutations. However, future preclinical trials are needed to evaluate the efficacy of such drugs in combating resistance evolution and to promote clearance of infections in animal models.

"We wanted to understand the molecular mechanism underlying the evolutionary arms race that pathogenic bacteria fight against our immune system and against antibiotics," says study lead author Susan Rosenberg of Baylor College of Medicine. "This is motivated by the hope of being able to make or identify a fundamentally new type of drug to slow down bacterial evolution." Not an antibiotic, which kills cells or prevents their proliferation, but an anti-involvent drug that would retard evolution, immune system and drugs to fight infections. "

To understand how antibiotics induce new mutations, first author John Pribis of Baylor College of Medicine, Rosenberg, and his team began exposing Escherichia coli to low doses of the antibiotic ciprofloxacin, which induces DNA breakage. Approximately 10% -25% of the cell population generated high levels of ROS, which transiently activated a pronounced response to stress.

But surprisingly, this stress response allowed the "player" subpopulation to shift the correction of DNA breaks from accurate to error prone, resulting in new mutations that promoted resistance to antibiotics never before encountered. According to the authors, the development of a subpopulation of transient gamblers may be a betting hedging strategy that could boost the evolution of resistance to new antibiotics without risk for most cells.

"This particular mechanism is probably important for resistance to quinolones – widely used antibiotics for which clinical resistance is common and occurs by new mutations in the clinic," says Rosenberg. "It is likely to also illuminate the formation of resistance to other antibiotics, in which the main route to resistance are new mutations, unlike antibiotics for which the main pathway is the acquisition of resistance genes from other bacteria."

In additional experiments, the researchers found that exposure to the ergo-reducing drug edaravone, which is approved for the treatment of stroke and amyotrophic lateral sclerosis, effectively inhibited the stress response and mutations induced by ciprofloxacin without altering antibiotic activity. "These data serve as a proof of concept for small molecule inhibitors that can be administered with antibiotics to reduce the evolution of resistance, preventing players from differentiating without harming antibiotic activity," says Rosenberg. "Edaravone is approved for human use, so if it is useful in pre-clinical testing, it can be accelerated for human testing because it has a known safety profile."

"Drugs like this could be used with standard antibiotics to slow the evolution of resistance," she says. "These could potentially extend the use of current antibiotics, and possibly function as mono-therapies, tilting the evolutionary battle in favor of the immune system."

In future studies, Rosenberg and his team will test whether anti-retroviral drugs prevent antibiotic resistance and improve clinical outcomes in animals infected with pathogenic bacteria. They also plan to look for additional drug targets. "This is not the only molecular mechanism of stress-induced mutagenesis," says Rosenberg. "We want to discover others that could be equally impressive in understanding and fighting the evolution of resistance."

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