Macrolones Could Make Bacterial Resistance 100 Million Times Harder

It is easy to view bacteria as among the planet's greatest scourges because of the illness and death they cause, and because they continually defeat our best antibiotics by evolving into drug-resistant superbugs.

Yet bacteria are simply doing what they have always done: discovering new ways to survive.

Combination therapies against antibacterial resistance

The hunt for new antibiotics continues, but combination treatments are also being tested more often. The aim is to shut down several bacterial escape routes simultaneously and reduce the opportunity for microbes to build resistance through successive biological workarounds.

How well such multi-pronged approaches will work against antibacterial resistance remains highly uncertain. One study identified antibacterial resistance as the third leading cause of death worldwide in 2019. Even so, this remains an essential strategy if the medicines we use are not to drive further antibiotic resistance.

A team of researchers in the US and China has now calculated that a new category of dual-action antibiotics could make the evolution of bacterial resistance 100 million times more difficult.

Known as macrolones, these synthetic compounds are based on older antibiotics first discovered in the 1950s. Following widespread use, bacteria quickly developed resistance to those earlier drugs.

After decades of drug development and researchers modifying chemical structures, a breakthrough arrived in 2010. Macrolones were created by attaching a quinolone side chain to the macrolide central ring, increasing their potency.

How macrolones target bacteria twice

The new compounds gained recognition for their "outstanding antibacterial profile" and their capacity to kill even drug-resistant bacterial strains. However, the molecular characteristics responsible for macrolones' enhanced properties were unknown.

To investigate, biological scientist Elena Aleksandrov of the University of Illinois Chicago (UIC) and her colleagues synthesised three new macrolones. They then examined their molecular structures to establish how the compounds disrupt crucial bacterial cell processes.

Their findings showed that macrolones kill bacteria through two mechanisms: they either interfere with a bacteria-specific enzyme that unwinds and refolds DNA during replication, or inhibit the ribosome, the cell's protein-making factory - or do both.

"The beauty of this antibiotic is that it kills through two different targets in bacteria," explains Alexander Mankin, UIC pharmaceutical scientist and senior author of the new study.

"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."

In addition, the macrolones eliminated bacteria grown in the laboratory without triggering any known resistance genes. They also displayed "dramatically improved activity" against recognised drug-resistant superbugs, including Streptococcus pneumoniae.

"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," structural biologist Yury Polikanov from UIC says.

Optimising dual-action antibiotics

However, further work is needed to strengthen the protection that these new dual-action antibiotics could provide against deadly, adaptable bacterial strains.

Resistance may be 'nearly impossible' according to the researchers' calculations, but the genetic strategies bacteria could deploy to overcome these new antibiotics should not be underestimated.

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

The study was published in Nature Chemical Biology.