Creating a defect in tRNA molecules could weaken bacteria’s two-pronged defense and help make faster-acting antibiotics
Antibiotic resistance is a major health threat, with about two million people in the U.S. getting an antibiotic-resistant infection per year, according to the Centers for Disease Control and Prevention (CDC). Gram negative bacteria, including types like E.coli and Salmonella, are often more difficult to kill because of their two-pronged defenses – they have two membranes rather than one, and also have numerous toxin pumps embedded in the membranes to expel any antibiotic that may have made it through. Now Jefferson researchers have uncovered how to target both of these defenses with one hit, which could help make antibiotics more effective.
“We showed that interfering with a transfer RNA (tRNA) 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 senior author Ya-Ming Hou, PhD, Professor of Biochemistry at the Sidney Kimmel Medical College at Jefferson (Philadelphia University + Thomas Jefferson University). The work was published in the journal Cell Systems.
tRNA molecules are not a typical antibiotic target. These molecules are part of the protein-building machinery that is essential for the daily function of cells in every living being. However, Dr. Hou’s team examined a kind of chemical “decoration” process in bacterial tRNAs that is absent from human cells. This difference between bacteria and humans makes this process a better drug target, since it’s less likely affect human cells.
tRNAs are decorated with chemical groups that are added on after tRNAs are synthesized in a cell. Dr. Hou’s group examined one such decoration, the addition of a methyl group to one particular location on the spine of several tRNAs. In earlier work, Dr. Hou’s lab showed that when these tRNAs were deficient in this one methylation, they were more likely to create errors in protein building. But not just any protein, the deficient tRNAs were particularly prone to mistakes at building proteins that sit within cell membrane.
This result made Dr. Hou think that perhaps a defect in the tRNA methylation might affect not only the bacteria’s toxin-pump, but a host of other types of proteins that help keep the membrane stable and cohesive.
In this paper, together with first author postdoctoral fellow Isao Masuda and others, Dr. Hou tested whether these defective tRNAs could make bacteria more susceptible to antibiotics, by creating bacteria that are genetically deficient in making the methyl-group decoration.
Through an elegant series of experiments, Dr. Hou’s team showed that these bacteria had membranes that were less cohesive and more permeable than normal. The bacteria with defective tRNAs were less effective at pumping out chemicals relative to the normal bacteria, suggesting that their toxin pumps were affected. Finally, the team showed that when the bacteria with defective tRNAs were exposed to various antibiotics, they died faster and were also less capable of developing drug resistance.
“Speed of killing is important in antibiotics,” says Dr. Hou. “The longer it takes for bacteria to die from antibiotics, the more likely they are to develop resistance.”
While pharmaceutical companies such as AstraZeneca and GSK have discovered compounds that can inhibit the enzyme from making the critical methylation on tRNAs, progress has stalled. The primary reason is that the inhibitors are unable to permeate through the bacterial membrane structure, which resonates with the major challenge confronting the entire field of antibiotic discovery.
Dr. Hou acknowledges the challenge. “First, we need to formulate the inhibitors in such a way as to be able to enter the cell more effectively,” says Dr. Hou. “Then, combining these inhibitors with traditional antibiotics to kill bacteria faster and reduce the likelihood of antibiotic resistance.”
At the moment, there are no drugs that can effectively attack this pathway. Dr. Hou’s lab is currently working on developing better inhibitors.
Learn more: Breaking Open the Gates of Antibiotic Resistance
The Latest on: Antibiotic resistance
via Google News
The Latest on: Antibiotic resistance
- Band-aids not helping with that infection? Try putting a virus on iton January 25, 2022 at 8:45 am
Even most of the ghastly life-forms on Monsters Inside Me have nothing on this. When a wound refused to heal despite round after round of antibiotics, the cure was a viral invasion. Wait. What? How ...
- Researchers discover a potential new way to combat antibiotic resistanceon January 25, 2022 at 5:37 am
Researchers from Monash University have discovered a potential new way to prevent antibiotic resistance and reduce antibiotic intake.
- Study: Drug-resistant bacteria kill 1.2 million people globallyon January 25, 2022 at 5:00 am
Antibiotic-resistant germs caused more than 1.2 million deaths globally in one year, according to new research that suggests that these “superbugs” have joined the ranks of the world’s lead ...
- Silent Pandemic: Antibiotic Resistant Infections Kill More People than Malariaon January 25, 2022 at 2:40 am
More than 1.2 million people died just last year in the world due to bacteria resistant to antimicrobial drugs , according to ...
- A Virus is Used to Cure Patient's Persistent Antibiotic-Resistant Infectionon January 22, 2022 at 7:53 am
Antibiotic-resistant infections pose a serious threat to human health, which is expected to get worse. Bacterial infections can be particularly deadly when | Microbiology ...
- Salt In My Soul: Poignant Film Calls Attention To The Need For Phages For Antibiotic Resistanceon January 22, 2022 at 6:39 am
Phage therapy could save many lives. Hopefully, sharing Mallory Smith's story will boost research into cystic fibrosis, growing antibiotic resistance, and the promise of phages.
- The Antibiotic Resistance Crisis: A Lead Cause In Global Deathson January 20, 2022 at 10:59 am
According to a study funded by the Bill and Melinda Gates Foundation, global antibiotic-resistant infections are a leading cause of global deaths whose full scale needs to be better understood.
- Seeking a hydrophilic nanoparticle solution to antibiotic resistanceon January 20, 2022 at 8:27 am
The Centers for Disease Control and Prevention estimates that more than 2.8 million Americans experience antibiotic-resistant infections each year; more than 35,000 die from those infections.
- Antibiotic-resistant infections are a ‘major global health threat’ that’s killing millions, scientists sayon January 20, 2022 at 3:16 am
A huge new global study found that drug-resistant bacterial infections played a part in almost 5 million deaths in 2019.
- Antibiotic resistance killed more people than malaria or AIDS in 2019on January 19, 2022 at 4:01 pm
About 1.3 million deaths were directly caused by drug-resistant bacterial infections in 2019, a global study estimates ...
via Bing News