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A “Knockdown” in the Fight Against Antibiotic Resistance

Written by: Ashley Koca

Antibiotic resistance has become a plague of its own, affecting millions and killing thousands. Thomas Jefferson University scientists have developed a new way to combat such detriment, utilizing m1 G37-tRNA methylation to cease the production of bacterial membrane-building proteins. The root of such resistance can be traced back to microorganisms having developed a double outer membrane as well as an efflux, expelling antibiotics. With the introduction of m1 G37-tRNA, scientists have discovered a possible new solution to the drug-resistance crisis.

To induce the deterioration of the efflux membrane, the researchers focused on proline (Pro) codons as the Pro amino acid controls the activity of the targeted membrane and polypeptide kinks. To drive the translation of the Pro codon, researchers knew the methylation of G37 on the 3’ end of tRNA must be present. In order to create mice with defective m1 G37-tRNA, scientists devised a method of understanding how m1 G37 controls translation using trmD-KD (knockdown) strains of bacteria—as it is necessary for viability and must be present. To do such, the original chromosomal trmD was deleted and replaced with human trm5. Knockdown is a universal determination factor of membrane protein effectiveness, the absence of such indicating a vitiated membrane barrier and efflux. The study’s findings indicated that the trmD-KD cells with induced m1 G37 deficiency had reduced cellular viability. Additionally, the study produced decreased antibiotic resistance from such depletions—a result highlighting the success of the study.

But what do these results mean for the future of medicine? In terms of current biotechnology, not much. Pharmaceutical companies have not yet developed a way to allow the necessary inhibitors to cross the efflux barrier. Since this hurdle has yet to be cleared, this discovery cannot be introduced into the commercial world. One way to combat this, though, would be to introduce the inhibitors as gentamicin-like molecules to infiltrate the membrane. The scientists suggested this solution as a way to surpass the cell’s protective TolC membrane protein, and once surpassed, inhibit the synthesis of the protein through trmD. This discovery should not be overlooked due to science’s current inability, but instead appreciated as a light illuminating future possibility through trmD determined Gram-negative biosynthesis. 

Work Cited

Masuda, I., Matsubara, R., Christian, T., Rojas, E. R., Yadavalli, S. S., Zhang, L., … Hou, Y.-M.

(2019). tRNA Methylation Is a Global Determinant of Bacterial Multi-drug Resistance. Cell Systems, 8(5), 475. doi: 10.1016/j.cels.2019.05.002

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