Dual action antibiotic could make bacterial resistance nearly impossible

A new antibiotic that works by destroying two different cellular targets could make it 100 million times harder for bacteria to develop resistance, according to new research from the University of Illinois at Chicago.

for New Paper in Nature Chemical BiologyThe researchers investigated how a synthetic drug called Makrolon works by disrupting bacterial cell function to fight infection. Experiments demonstrated that Makrolon works in two different ways: by blocking protein production or by disrupting DNA structure.

because Bacteria The researchers calculated that defenses against both attacks would need to be implemented simultaneously. Drug resistance It’s almost impossible.

“The beauty of this antibiotic is that it kills two different targets in bacteria,” said Alexander Mankin, distinguished professor of pharmacology at UIC. “If the antibiotic attacks both targets at the same concentration, the bacteria will acquire random mutations in one of the two targets and lose the ability to develop resistance.”

Macrolones are synthetic antibiotics that combine the structures of two widely used antibiotics with different mechanisms of action. Macrolides, such as erythromycin, inhibit ribosomes, the cell’s protein-making factories. Fluoroquinolones, such as ciprofloxacin, target a bacterial enzyme called DNA gyrase.

Two UIC laboratories, led by Yuri Polikanov, associate professor of biological sciences, and Mankin and Nora Vásquez-Lathrop, professors of pharmaceutical research, investigated the cellular activity of various macrolon drugs.

Polikanov’s group Structural Biologystudied how these drugs interact with ribosomes and found that they bind more strongly than conventional macrolides, which were even able to bind and block the ribosomes of macrolide-resistant bacterial strains, failing to trigger the activation of resistance genes.

Other experiments tested whether the macrolon drugs preferentially inhibited ribosomal or DNA gyrase enzymes at various doses, and while many designs excelled at inhibiting one target or the other, those that inhibited both at the lowest effective dose stood out as the most promising candidates.

“The advantage of attacking two targets at essentially the same concentration is that it makes it nearly impossible for the bacteria to easily come up with a simple genetic defense,” Polikanov said.

The work also reflects the interdisciplinary collaboration at UIC’s Molecular Biology Building, where researchers from the Schools of Medicine, Pharmacy, and the Humanities and Sciences share nearby labs to drive basic science discoveries like this one, the authors note.

“The upshot of this work is that we now know how to go about doing this,” Mankin said. “What we’re saying to chemists is that we need to optimize these macrolones to hit both targets.”

In addition to Mankin, Polikanov and Vásquez-Lathrop, co-authors from UIC include Elena Alexandrova, Dorota Klepaki and Faezeh Alizadeh.