A new antibiotic that works by disrupting two different cellular targets would make it 100 million times more difficult for bacteria to evolve resistance, according to new research from the University of Illinois Chicago.
Antimicrobial resistance (AMR) is one of the top global public health and development threats. It is estimated that bacterial AMR was directly responsible for 1.27 million global deaths in 2019 and contributed to 4.95 million deaths. AMR puts many of the gains of modern medicine at risk. It makes infections harder to treat and makes other medical procedures and treatments – such as surgery, caesarean sections and cancer chemotherapy – much riskier. If this was not solved there would be an antibiotics pipeline and access crisis. There is an inadequate research and development pipeline in the face of rising levels of resistance, and urgent need for additional measures to ensure equitable access to new and existing vaccines, diagnostics and medicines. In addition to death and disability, AMR has significant economic costs. The World Bank estimates that AMR could result in US$ 1 trillion additional healthcare costs by 2050, and US$ 1 trillion to US$ 3.4 trillion gross domestic product (GDP) losses per year by 2030.
“The beauty of this antibiotic is that it kills through two different targets in bacteria,” said Alexander Mankin, distinguished professor of pharmaceutical sciences at UIC. “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.”
Macrolones are synthetic antibiotics that combine the structures of two widely used antibiotics with different mechanisms. Macrolides, such as erythromycin, block the ribosome, the protein-manufacturing factories of the cell. Fluoroquinolones, such as ciprofloxacin, target a bacteria-specific enzyme called DNA gyrase.
Two UIC laboratories led by Yury Polikanov, associate professor of biological sciences, Mankin and Nora Vázquez-Laslop, research professor of pharmacy, examined the cellular activity of different macrolone drugs.
Polikanov’s group, which specializes in structural biology, studied how these drugs interact with the ribosome and found that they bind more tightly than traditional macrolides. The macrolones were even capable of binding and blocking ribosomes from macrolide-resistant bacterial strains and failed to trigger the activation of resistance genes.
Other experiments tested whether the macrolone drugs preferentially inhibited the ribosome or the DNA gyrase enzymes at various doses. While many designs were better at blocking one target or another, one that interfered with both at its lowest effective dose stood out as the most promising candidate.
Studies show the cost of resistant infection ranges is up to about $30,000 per patient episode (2020 dollars and costs). On average people stay an extra 7.4 days in the hospital and the odds of dying nearly double (1.84 times) and there is about 1.492 increased readmission likelihood.
Keep reading with a 7-day free trial
Subscribe to next BIG future to keep reading this post and get 7 days of free access to the full post archives.