A University of Saskatchewan (U of S) research team has discovered a way to prevent bacteria from developing resistance to antibiotics, potentially helping to blunt the edge of a looming threat to public health around the world.
"Bacteria have a remarkable ability to acquire resistance against antibiotics," said U of S biochemist Ron Geyer, who led the study published in the journal Cell Chemical Biology. "We need new strategies to block development of resistance and to prolong the life of antibiotics, and we believe our work has revealed a promising direction."
It's an urgent problem. In 2014, the World Health Organization reported that antibiotic resistance "is now a major threat to public health," and warned of a return to a pre-antibiotic era, where "common infections and minor injuries which have been treatable for decades can once again kill."
The U of S team looked at the "SOS response," which happens when bacteria are attacked by antibiotics. The bacterial cell stops its normal cycle in order to repair its DNA. The process is quite error-prone, so there are a lot of mutations -- plus the response allows the bacteria to pick up genes from other bacteria in a process called horizontal gene transfer.
Since there are millions of bacteria, there are bound to be a few whose mutations that make some of them resistant to antibiotics. These resistant bacteria survive and multiply.
Geyer and his team looked at the molecular "switching system" for the SOS response -- the RecA enzyme that turns it on, and the LexA enzyme that keeps it turned off. The team developed compounds that inhibit the RecA "on" switch. This prevented the SOS response, made the antibiotics more effective, reduced mutations, and blocked horizontal gene transfer.
The team tested the RecA inhibitors both with a variety of lab bench assays and in mice against several bacteria, including two that are notorious for multi-drug resistance: Pseudomonas aeruginosa and Staphylococcus aureus.
"Our results suggest the inhibitors should be useful with a broad spectrum of bactericidal antibiotics in Gram-negative or Gram-positive bacteria," Geyer said.
He cautioned that much work remains to be done, for example, to tailor methods to better deliver RecA inhibitors.
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