‘Dialling down bacterial resistance’ – Written by Charlotte Harrison, Science Writer.
A paper published in Science Advances has identified a drug that at low doses slows the ability of bacteria to develop antibiotic resistance. The study provides proof-of-concept for evolution-slowing drugs that can prolong antibiotic effectiveness.
The drug, dequalinium, is approved for human use for other indications, so clinical trials of this antibiotic-boosting strategy should be feasible in the future.
Slowing evolution
The authors reasoned that ideal targets for evolution-slowing drugs might include the hubs of the protein networks that underpin antibiotic-induced mutagenesis. Two such hubs are the SOS DNA damage response and the σS general stress response.
They screened a small-molecule library of 1120 drugs approved for human use to identify those that inhibited SOS or general responses, and identified four compounds.
These compounds were then characterised further in an E. coli-based assay that measured the level of new gene mutations — a key driver of bacterial resistance — in the presence of the commonly used antibiotic ciprofloxacin. In this assay, dequalinium reduced the speed at which new mutations were formed, and did so at concentrations 100 times lower than those used clinically.
Inhibiting the starvation response
Mechanistically, the authors found that dequalinium inhibited activation of the E. coli general stress response, which would otherwise promote ciprofloxacin-induced (that is, stress-induced) mutagenic DNA break repair. More specifically, dequalinium inhibited the activation of the upstream stringent starvation stress response.
Importantly, dequalinium slowed bacterial evolution without favouring the proliferation of dequalinium-resistant mutants – in other words, the bacteria did not develop resistance to the drug.
Finally, the authors showed that bacterial mutagenesis occurred in a mouse infection model, and that dequalinium reduced the frequency of bacterial mutants.
Antibiotic-free?
The study indicates that dequalinium might be used during antibiotic treatment to slow the emergence of resistance. Interestingly, the authors note that evolution-slowing drugs might make it possible to treat infections without antibiotics. Slowing pathogen evolution with drugs such as dequalinium might allow the host immune response to outstrip the activity of the pathogen to allow clearance of infections, they said.
