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Break open the gates of antibiotic resistance



  salmonella
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Antibiotic resistance is a major health risk where about two million people in the United States receive an antibiotic-resistant infection. Years, according to the Centers for Disease Control and Prevention (CDC). Gram-negative bacteria, including types such as E. coli and Salmonella, are often more difficult to kill due to their triangular defenses ̵

1; they have two membranes rather than one and also have several toxin pumps embedded in the membranes to display any antibiotic that may have passed through it. Now, Jefferson scientists have uncovered how to target both of these defenses with a hit, which could help make antibiotics more effective.


"We showed that interfering with a transfer RNA (tRNA) molecule in a way unique to bacteria, fights the ability of the bacterial cell to produce membrane proteins required for the drug barrier and efflux activity," said senior author Ya-Ming Hou. Ph.D., Professor of Biochemistry at 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 machine that is essential for the daily functioning of cells in any living being. Dr. However, the Hou & # 39; team investigated some kind of chemical "decoration" process in bacterial tRNAs that are absent from human cells. This difference between bacteria and humans makes this process a better drug target as it is less likely to affect human cells.

tRNAs are decorated with chemical groups added after tRNA & # 39; are synthesized in a cell. Dr. Hous group examined such a decoration, the addition of a methyl group to a particular site on the back of several tRNAs. In previous work, Dr. Hou & # 39; s lab that when these tRNA & # 39; were deficient in this one methylation, they were more likely to create protein build-up errors. But not just any protein, the defective tRNAs were particularly prone to making mistakes by building proteins within the cell membrane.

This result did Dr. Hou believe that perhaps a defect in the tRNA methylation can affect not only the bacteria's toxin pump, but a host of other types of proteins that help keep the membrane stable and coherent.

In this paper, Dr. Hou, together with first author Postdoctor Isao Masuda and others, about these defective tRNAs are able to make bacteria more susceptible to antibiotics by creating bacteria that are genetically deficient in the production of the methyl group.

Dr. Hou's team showed through an elegant series of experiments that these bacteria had membranes that were less cohesive and more permeable than normal. The bacteria with defective tRNAs were less effective at pumping chemicals over 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 able to develop drug resistance.

"The rate 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 like AstraZeneca and GSK have discovered compounds that can inhibit the enzyme from making the critical methylation at tRNA & # 39; progress has stopped. 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 area of ​​antibiotic search.

Dr. Hou recognizes the challenge. "First, we must formulate the inhibitors in such a way that they can enter the cell more effectively," says Dr. Hou. "So, these inhibitors combine with traditional antibiotics to kill bacteria faster and reduce the likelihood of antibiotic resistance."

Currently, there are no drugs that can effectively attack this pathway. Dr. Hou's lab is currently developing better inhibitors.


Scientists discover a new mechanism used by bacteria to evade antibiotics


More information:
Isao Masuda et al. tRNA methylation is a global determinant of bacterial multi-drug resistance, Cell Systems (2019). DOI: 10.1016 / j.cels.2019.03.008

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Thomas Jefferson University

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Break open the gates of antibiotic resistance (2019, April 30)
April 30, 2019
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