Breaking new ground, scientists from the University of Illinois Chicago claim to have fashioned one of the most radical antibiotics to date. Revealed in the new study set forth by Nature Chemical Biology, the new drug operates a two-pronged mechanism of action on two important bacterial actions simultaneously, making it 100 million times harder for bacteria to start developing resistance.
“The antibiotic, part of a new class known as macrolones, interferes with protein production and corrupts DNA structure, thus making both a double blow against bacterial cell function. This seriously impairs the adapting and survival abilities of bacteria. ‘The beauty of this antibiotic is that it kills through two different targets in bacteria,’ commented Alexander Mankin, a distinguished professor of pharmaceutical sciences at UIC.”. He explained that when the antibiotic hits two targets at the same concentration, bacteria lose their ability to become resistant through random mutations in either of the two targets.
Macrolones are synthetic compounds integrating the structures of two very different and highly used antibiotics: one is the macrolide erythromycin, which blocks the ribosome, an enzyme that synthesizes proteins, and the other is the quinolones, among which quinolone ciprofloxacin is included; it targets the bacterial enzyme that is necessary for the replication of DNA, known as DNA gyrase.
Two laboratories at UIC, including that of Yury Polikanov, associate professor of biological sciences, and Mankin and Nora Vázquez-Laslop, research professor of pharmacy, studied the molecular behavior of this class of drugs in complex with their bacterial targets. Using structural biology approaches, the team led by Polikanov has identified the mode and specific binding site of macrolones on the ribosome. It was discovered that macrolones could bind more firmly to the ribosome than traditional macrolides. Surprisingly, they turned out to be effective against macrolide-resistant strains of bacteria, explaining.
Additional experiments tested whether macro lines were inhibiting ribosomes or DNA gyrase more effectively at different doses. One design in particular, though, stood out, in Polikanov’s words, “hitting both mechanisms at its lowest effective dose.” If a drug hits two targets at the same concentration, he reasons, then the bacteria can’t come up with a simple genetic defense.
The study emphasizes how the UIC Molecular Biology Research Building brings together interdisciplinary researchers for the advancement of scientific discoveries. Mankin said the take-home of this work is an understanding of how to move forward and, in general, the guidance given to chemists to optimize these macrolones to hit both targets.
This very creative dual-target antibiotic represents a new promised avenue in the fight against bacterial infection and drug resistance. Other UIC authors on this interdisciplinary research team include Elena Aleksandrova, Dorota Klepacki, and Faezeh Alizadeh, who were quoted as contributing significantly to the process of optimization of macrolones before their use in future therapeutic testing. If further developed, this is going to be one of the most impactful breakthroughs in the fight against antibiotic-resistant bacteria.