A new antibiotic that works by disrupting two different cellular targets would make it 100 million times harder for bacteria to develop resistance, according to new research from the University of Illinois at Chicago.
For a new paper In Nature Chemical Biology, researchers studied how a class of synthetic drugs called macrolones disrupts the functioning of bacterial cells to fight infectious diseases. Their experiments show that macrolones can work in two different ways: either by interfering with protein production or by corrupting the structure of DNA.
Since bacteria would have to implement defenses against both attacks simultaneously, the researchers calculated that drug resistance is nearly impossible.
“The beauty of this antibiotic is that it kills two different targets in bacteria,” said Alexander MankinUIC professor emeritus of pharmaceutical sciences. “If the antibiotic hits both targets at the same concentration, the bacteria lose their ability to become resistant by acquiring random mutations in one of the two targets.”
Macrolones are synthetic antibiotics that combine the structures of two widely used antibiotics with different mechanisms. Macrolides, such as erythromycin, block the ribosome, the cell’s protein-making factory. Fluoroquinolones, such as ciprofloxacin, target a bacteria-specific enzyme called DNA gyrase.
Two UIC laboratories led by Yuri Polikanovassociate professor of biological sciences, and Mankin and Nora Vázquez-Laslopprofessor and researcher in pharmacy, examined the cellular activity of different macrolone-based drugs.
Polikanov’s group, which specializes in structural biology, studied how these drugs interact with the ribosome and found that they bind more tightly than traditional macrolides. The macrolides were even able to bind and block the ribosomes of macrolide-resistant bacterial strains and failed to trigger the activation of resistance genes.
Further experiments tested whether macrolone drugs preferentially inhibited ribosome or DNA gyrase enzymes at different doses. While many models were more effective at blocking one target or the other, the one that interfered with both at its lowest effective dose emerged as the most promising candidate.
“By essentially hitting two targets at the same concentration, the advantage is that you make it almost impossible for bacteria to easily find a simple genetic defense,” Polikanov said.
The study also reflects the interdisciplinary collaboration within UIC’s Molecular Biology Research Building, where researchers from the colleges of medicine, pharmacy and liberal arts and sciences share neighboring labs and drive fundamental scientific discoveries like this one, the authors said.
“The main outcome of all this work is understanding how we need to move forward,” Mankin said. “And what we’re getting chemists to understand is that we need to optimize these macrolones to hit both targets.”
In addition to Mankin, Polikanov and Vázquez-Laslop, co-authors of the UIC paper include Elena Aleksandrova, Dorota Klepacki and Faezeh Alizadeh.
Written by Rob Mitchum
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