A groundbreaking study from the University of Illinois Chicago (UIC) has unveiled a new antibiotic with the potential to make it nearly impossible for bacteria to develop resistance. This innovative drug, detailed in a recent paper in Nature Chemical Biology, works by simultaneously targeting two crucial bacterial cellular processes, making it 100 million times more difficult for bacteria to evolve defenses.
The researchers explored a class of synthetic antibiotics called macrolones, which have the unique ability to disrupt bacterial cell function through two different mechanisms: interfering with protein production and corrupting DNA structure. This dual-action approach significantly complicates the bacteria’s ability to adapt and survive.
“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.”
The Mechanisms Behind Macrolones
Macrolones are synthetic compounds that merge the structures of two widely used antibiotics with distinct mechanisms. Macrolides, such as erythromycin, inhibit the ribosome, the cellular machinery responsible for protein synthesis. Fluoroquinolones, like ciprofloxacin, target DNA gyrase, an enzyme essential for bacterial DNA replication.
Two UIC laboratories, led by Yury Polikanov, associate professor of biological sciences, and Mankin and Nora Vázquez-Laslop, research professor of pharmacy, investigated how macrolone drugs interact with these bacterial targets. Polikanov’s team, specializing in structural biology, found that macrolones bind more tightly to the ribosome than traditional macrolides. Remarkably, macrolones were also effective against macrolide-resistant bacterial strains, preventing the activation of resistance genes.
Promising Results and Future Directions
Further experiments assessed whether macrolones were more effective at inhibiting ribosomes or DNA gyrase at various doses. One particular design emerged as a standout, effectively targeting both mechanisms 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.
The study underscores the importance of interdisciplinary collaboration at the UIC Molecular Biology Research Building, where researchers from diverse fields work together to drive scientific discoveries.
“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.”
Conclusion
This innovative dual-target antibiotic offers a promising new approach to combating bacterial infections and drug resistance. The interdisciplinary team at UIC, including co-authors Elena Aleksandrova, Dorota Klepacki, and Faezeh Alizadeh, has provided crucial insights into optimizing macrolones for future therapeutic use. With further development, this breakthrough could significantly impact the fight against antibiotic-resistant bacteria.
By Impact Lab
