One-two punch weakens bacteria's defenses against antibiotics
Bacteria are quickly evolving resistances to antibiotics, to the extent that our best drugs might not work in the terrifyingly-near future. Scientists are hard at work developing new antibiotics, or finding ways to make existing ones more effective. Now, researchers from Thomas Jefferson University have found a new way to weaken bacterial defenses, slowing down the development of antibiotic resistance.
The team is targeting gram-negative bacteria, a class of bugs that includes famous faces like E. coli and Salmonella. These organisms can be tricky to kill, thanks to their two-pronged defense systems – their double-layered cell membranes do a better job of keeping antibiotics at bay, and if any drug particles do make it through, they can pump them back out.
But the Jefferson team discovered a way to disable both defenses at once. The key lies in transfer RNA (tRNA) molecules, which play a part in building proteins vital for cell function. In earlier work, the researchers discovered that depriving tRNAs of a particular chemical group caused them to make more errors when building certain proteins. Those proteins, it turns out, help stabilize cell membranes and keep those toxin pumps working – so messing with them could weaken bacterial defenses.
In the new study, the team tested this idea by engineering strains of E. coli and Salmonella that had "defective" tRNA molecules. Sure enough, the bacteria were found to have less cohesive cell membranes than usual, meaning more outside fluids could pass through, and the bugs had a harder time pumping out toxins. As a result, when they were exposed to various antibiotics they died faster, reducing the likelihood of them developing resistance.
Another benefit of the technique is that while tRNAs are at work in all living cells, the targeted chemical groups are only present in bacteria. That means a drug designed to interfere with them wouldn't harm human cells.
"We showed that interfering with a transfer RNA molecule, in a way that is unique to bacteria, cripples the bacterial cell's ability to make membrane proteins required for the drug barrier and efflux activity," says Ya-Ming Hou, senior author of the study. "Speed of killing is important in antibiotics. The longer it takes for bacteria to die from antibiotics, the more likely they are to develop resistance."
As it stands the study is a proof of concept, but there are some challenges to overcome before it could be used as a clinical technique. The team had to engineer bacteria to have defective tRNA molecules – in the wild the bacteria can make the proteins perfectly fine. Now that the target has been identified, the next steps are to develop drugs that can interfere with the process.
The research was published in the journal Cell Systems.
Source: Thomas Jefferson University