Macrolones Offer Promising Strategy for Combating Resistant Bacteria

New research from the University of Illinois Chicago suggests that a novel antibiotic that disrupts two distinct cellular targets would make it 100 million times harder for bacteria to evolve resistance.

A class of synthetic drugs known as macro lines disrupts the function of bacterial cells to combat infectious diseases. This was the subject of a recent paper published in Nature Chemical Biology. Their research shows that macro lines can function by either destroying DNA structure or interfering with the synthesis of proteins.

The researchers concluded that drug resistance is almost impossible because bacteria would have to develop defences against both attacks at the same time.

The beauty of this antibiotic is that it kills through two different targets in bacteria. 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.”

Alexander Mankin, Distinguished Professor, Pharmaceutical Sciences, University of Illinois Chicago

Synthetic antibiotics known as macrolones combine the structures of two commonly used antibiotics with distinct mechanisms. Macrolides, like erythromycin, inhibit the ribosome, which is the cell's factory for producing proteins. Fluoroquinolones, like ciprofloxacin, work by targeting DNA gyrase, an enzyme that is unique to bacteria.

Researchers at the University of Illinois Chicago (UIC), led by Dr. Yury Polikanov (Associate Professor of Biological Sciences), Mankin, and Dr. Nora Vázquez-Laslop (Research Professor of Pharmacy), investigated how different macrolone drugs affect the inner workings of bacterial cells. 

Structural biology experts Polikanov's group investigated the interaction between these drugs and the ribosome and discovered that they bind more tightly than conventional macrolides. Even bacterial strains resistant to macrolides could bind and block ribosomes produced by the macrolones, and they were unable to cause the activation of resistance genes.

Additional tests examined whether, at different doses, the macrolone medications preferentially inhibited the DNA gyrase or the ribosome. Although numerous designs demonstrated superiority in blocking specific targets, the most promising candidate was the one that interfered with both at the 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.”

Yury Polikanov, Associate Professor, Biological Sciences, University of Illinois Chicago

According to the authors, the study also highlights the multidisciplinary cooperation at the UIC Molecular Biology Research Building, where scientists from the colleges of medicine, pharmacy, and liberal arts and sciences collaborate in adjacent labs to produce groundbreaking scientific discoveries.

The main outcome from all of this work is the understanding of how we need to go forward. And the understanding that we’re giving to chemists is that you need to optimize these macrolones to hit both targets.”

Alexander Mankin, Distinguished Professor, Pharmaceutical Sciences, University of Illinois Chicago