A groundbreaking discovery from the University of Illinois Chicago (UIC) has revealed a new antibiotic that targets bacteria in two different ways, making it nearly impossible for bacteria to develop resistance.
This dual-action antibiotic could revolutionize how we fight infectious diseases.
The research, published in the journal Nature Chemical Biology, focuses on a class of synthetic drugs called macrolones.
These drugs disrupt bacterial cell function by interfering with both protein production and DNA structure.
Because bacteria would need to simultaneously defend against both attacks, the likelihood of developing resistance is drastically reduced.
“The beauty of this antibiotic is that it kills through two different targets in bacteria,” said Alexander Mankin, a distinguished professor of pharmaceutical sciences at UIC.
“If the antibiotic hits both targets at the same concentration, then the bacteria lose their ability to become resistant via acquisition of random mutations in any of the two targets.”
Macrolones are synthetic antibiotics that combine the structures of two widely used antibiotics, each with a different mechanism of action.
Macrolides, like erythromycin, block the ribosome, which is the protein manufacturing factory of the cell. Fluoroquinolones, like ciprofloxacin, target a bacteria-specific enzyme called DNA gyrase.
The study was conducted by two UIC laboratories led by Yury Polikanov, an associate professor of biological sciences, and Mankin and Nora Vázquez-Laslop, a research professor of pharmacy. The team examined how macrolone drugs interact with bacterial cells.
Polikanov’s group, which specializes in structural biology, discovered that macrolones bind more tightly to the ribosome than traditional macrolides. They found that macrolones could even block ribosomes in macrolide-resistant bacterial strains without triggering the activation of resistance genes.
Other experiments tested whether macrolone drugs were more effective at inhibiting the ribosome or the DNA gyrase enzyme at various doses.
While many designs were better at blocking one target over the other, the most promising candidate was a drug that effectively interfered with both targets at its lowest effective dose.
“By basically hitting two targets at 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 explained.
This study highlights the importance of interdisciplinary collaboration at UIC. Researchers from the colleges of medicine, pharmacy, and liberal arts and sciences, who share neighboring laboratories in the UIC Molecular Biology Research Building, played key roles in this discovery.
“The main outcome from all of this work is the understanding of how we need to go forward,” Mankin said. “And the understanding that we’re giving to chemists is that you need to optimize these macrolones to hit both targets.”
In addition to Mankin, Polikanov, and Vázquez-Laslop, the UIC team included researchers Elena Aleksandrova, Dorota Klepacki, and Faezeh Alizadeh.
This new antibiotic represents a significant step forward in the fight against bacterial infections, offering hope for a future where antibiotic resistance is no longer a major threat.
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