University of Colorado, Boulder, team lead Anushree Chatterjee (right), with first author Colleen Courtney (left) and Peter Otoupal, a member of the Chatterjee lab (center). [Image: University of Colorado, Boulder]
Multidrug-resistant (MDR) bacterial infections are a growing cause of concern worldwide. The World Health Organization highlighted the severity of this problem by designating drug-resistant strains of Escherichia coli and Klebsiella pneumoniae “priority 1 critical class bacterial pathogens in urgent need of effective antibiotics.”
Now, a team of researchers from the University of Colorado Boulder, USA, reports that it has developed a platform based on intracellular light-activated quantum dots (QDs) that could help address the problem. In the method, the QDs work inside living cells to generate a superoxide that acts as a kind of sucker punch, weakening the bacteria and making the superbugs more vulnerable to existing antibiotics (Sci. Adv., doi: 10.1126/sciadv.1701776).
According to the Boulder team, its QD platform reduced antibiotic resistance by a factor of 1,000 in in vitro multidrug-resistant (MDR) isolate infections. In animal model demonstrations with Caenorhabditis elegans (a microscopic worm), the combination of superoxide-generating QDs with the antibiotic ciprofloxacin reduced the bacterial load in the worm’s gut more than treatment with the antibiotic alone. Team lead Anushree Chatterjee says that the QD platform could someday offer clinicians “an adaptable, multifaceted approach to fighting infections that are already straining the limits of current treatments.”
Overwhelming bacterial defenses
Reactive oxygen species (ROS) are present in low levels during normal bacterial aerobic respiration. Bacteria control ROS levels by producing antioxidants. However, elevated ROS levels can overwhelm a bacterium’s antioxidant defense; such oxidative stress is toxic and causes damage to the bacterium’s DNA.
The method of Chatterjee and her colleagues exploits ROS toxicity by using engineered QDs to produce, on-demand, an overwhelming amount of intracellular superoxide (a particularly harmful ROS). That superoxide flood, they say, weakens MDR bacteria and makes the bugs more susceptible to existing antibiotics.
The group’s “tailored redox potential” QDs are made of cadmium telluride and are small enough (less than 3 nm in diameter) to easily enter bacteria through holes in the cell wall. The QDs can be turned on and off with a specific wavelength of light, and their oxidation potential is tuned for superoxide radicals from molecular oxygen.
Delivering the punch
During in vitro tests with clinical MDR isolates in E. coli, K. pneumoniae and Salmonella enterica, the researchers found that combining their superoxide-producing QDs with antibiotics produced a synergistic interaction in more than 75 percent of the tests. Within those synergistic combinations, they observed a reduction in the effective antibiotic resistance of the clinical isolate infections by a factor of 1,000. During animal model demonstrations with C. elegans, the researchers found that a worm’s chance of surviving an MDR bacterial infection increased when it was treated with a combination of superoxide-generating QDs and ciprofloxacin compared to only ciprofloxacin.
The team says the results from its tests on clinical MDR isolates and demonstrations with C. elegans “highlight the ability to engineer superoxide generation to potentiate antibiotic activity and combat highly drug-resistant bacterial pathogens.”
The researchers say that their QD technology, unlike previous antibiotic treatments, can work intracellularly with a high level of specificity. Chatterjee adds that the QDs are inexpensive, don’t require developing new antibiotics, and are very easily scaled up—a big advantage over conventional small-molecule-based antibiotics. The team sees its QDs eventually being used as a technology platform for treating a wide variety of infections and for other therapeutic applications.