Chicago, IL – Bacteria long considered one of humanity’s greatest adversaries due to their role in causing diseases and evolving into drug-resistant superbugs, may soon face a formidable challenge. Scientists from the United States and China have developed a new class of dual-action antibiotics called macrolones, which could make it 100 million times more difficult for bacteria to develop resistance.
Antibiotic resistance has become a global health crisis, with resistant bacteria causing millions of deaths annually. A study in 2019 found it to be the third leading cause of death worldwide. Traditional antibiotics are becoming increasingly ineffective as bacteria rapidly evolve to thwart them.
In response, researchers have been exploring combination therapies that target multiple bacterial pathways simultaneously, reducing the likelihood of bacteria developing resistance. These multi-pronged approaches are crucial to prevent further resistance and ensure the effectiveness of existing antibiotics.
Macrolones, synthetic compounds derived from older antibiotics discovered in the 1950s, represent a significant breakthrough. Despite their initial effectiveness, these older antibiotics quickly became obsolete due to bacterial resistance. In 2010, researchers enhanced these compounds by adding a quinolone side chain to the macrolide central ring, significantly improving their potency.
A team led by biological scientist Elena Aleksandrov from the University of Illinois Chicago (UIC) synthesized three new macrolones and analyzed their molecular structures. They discovered that macrolones attack bacteria in two ways: by inhibiting an enzyme essential for DNA replication and by targeting the ribosome, the cell’s protein production machinery.
“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 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.”
The study revealed that macrolones effectively killed lab-grown bacteria without activating known resistance genes. They showed dramatically improved activity against drug-resistant superbugs, including Streptococcus pneumoniae, a significant cause of pneumonia and other infections.
“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,” says structural biologist Yury Polikanov from UIC.
Despite the promising results, researchers caution against underestimating bacteria’s ability to evolve. While the dual-action mechanism significantly reduces the likelihood of resistance, bacteria may still find ways to adapt. Continued research and optimization of macrolones are essential to reinforce their efficacy against deadly bacterial strains.
“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 has been published in Nature Chemical Biology, marking a significant step forward in the fight against antibiotic resistance. The development of macrolones offers hope for a future where bacterial infections can be effectively treated, despite the relentless evolution of these microscopic adversaries.
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