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, Chicago.
In for a new piece of paper Nature Chemical BiologyResearchers investigated how a class of synthetic drugs called macrolones disrupt bacterial cell function to fight infectious diseases. Their experiments show that macrolones can work in two different ways: by disrupting protein production or by corrupting DNA structure.
Because bacteria would have to implement defenses against both attacks simultaneously, the researchers calculated that drug resistance is virtually impossible.
“The great thing about this antibiotic is that it kills via two different targets in bacteria,” said Alexander Mankin, professor of pharmaceutical sciences at UIC. “If the antibiotic hits both targets at the same concentration, the bacteria lose their ability to become resistant via acquiring random mutations in one of the two targets.”
Macrolones are synthetic antibiotics that combine the structures of two commonly used antibiotics with different mechanisms. Macrolides, such as erythromycin, block the ribosome, the cell’s protein production factories. Fluoroquinolones, such as ciprofloxacin, target a bacteria-specific enzyme called DNA gyrase.
Two UIC laboratories led by Yury Polikanov, associate professor of biological sciences, and Mankin and Nora Vázquez-Laslop, research professor of pharmacy, examined the cellular activity of several macropulmonary 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 macrolones were even able to bind and block ribosomes of macrolide-resistant bacterial strains and failed to induce the activation of resistance genes.
Other experiments tested whether the macrolone drugs preferentially inhibited the ribosome or DNA gyrase enzymes at different doses. While many designs were better at blocking one target or the other, a design that disrupted both at the lowest effective dose emerged as the most promising candidate.
“By essentially hitting two targets with the same concentration, the advantage is that you make it almost impossible for the bacteria to easily come up with a simple genetic defense,” Polikanov said.
The study also reflects the interdisciplinary collaboration in the UIC Molecular Biology Research Building, where researchers from the colleges of medicine, pharmacy and liberal arts and sciences share adjacent laboratories and drive fundamental scientific discoveries like this, the authors said.
“The most important outcome of all this work is the understanding of how to move forward,” Mankin said. “And the insight we give chemists is that you have to optimize these macro wages to achieve both goals.”
In addition to Mankin, Polikanov and Vázquez-Laslop, UIC co-authors on the paper include Elena Aleksandrova, Dorota Klepacki and Faezeh Alizadeh.
