With the growth and spread of “superbugs,” bacteria resistant to multiple drugs, the world is quickly approaching a post-antibiotic era defined by incurable bacterial infections. To try to avoid this fate, researchers have devised alternative means to kill these hardy bacteria, such as using different types of nanoparticles, with varying degrees of success.
In a major step toward this goal, scientists at the University of Colorado Boulder (UCB) have developed photoexcitable (light-activated) quantum dots that can effectively and specifically kill superbugs without harming mammalian cells. The semiconductor nanoparticles, described recently in Nature Materials (DOI: 10.1038/NMAT4542), were able to kill 92% of multidrug-resistant bacteria in culture tests.
“The problem of superbugs is current, it’s real, it’s alarming,” said study co-lead author Anushree Chatterjee, a chemical engineer at UCB. “We are out of antibiotics and we really, really need therapeutics that can work. This invention is important for this reason, and we have an extreme need to move forward to clinical trials.”
The overuse and misuse of antibiotics has recently led to a global epidemic of drug-resistant bacteria. In the United States alone, superbug infections affect nearly two million people and kill at least 23,000 each year, according to the Centers for Disease Control and Prevention. Some strains of bacteria, such as Neisseria gonorrhoeae (gonorrhea) and Klebsiella, are resistant to nearly all antibiotics, rendering them nearly untreatable.
Various research groups have investigated nano-therapeutics—in particular, light-activated metal nanoparticles that destroy bacteria through heat or other means—as a replacement for antibiotics. While they are sometimes effective in killing superbugs, a common problem with these approaches is their non-specificity, or the propensity for the nano-therapeutics to be toxic to or damage mammalian cells.
A different and promising approach with nano-therapeutics is to use them to attack superbugs with reactive oxidative species. Aerobic bacteria are able to mitigate or use free oxidative species to survive, but introducing specific oxidative species, such as superoxide radicals and peroxide, can disrupt the bacteria’s redox homeostasis and cause cell death; various antibiotics, such as ampicillin, gentamicin, and ciprofloxacin, are known to work through a similar process.
Light-activated cadmium telluride nano-particle quantum dot (shown here in a high-resolution transmission electron micrograph with a scale bar of 2 nm) designed to kill a number of multidrug-resistant bacteria without harming mammalian cells. Credit: Chatterjee and Nagpal labs, University of Colorado Boulder.
While trying to develop intelligent, non-natural therapeutics to target antibiotic-resistant bacteria, Chatterjee teamed up with UCB chemical engineer Prashant Nagpal, co-lead author who was initially working on developing nanoelectronic techniques for single-molecule DNA and RNA sequencing. “During those studies, we realized that these strains have a propensity to be susceptible when there is oxygen present in the aqueous media,” Nagpal said. “The superbugs are susceptible to certain potentials and radicals, so let’s go back and design nanoparticles that make use of that.”
Chatterjee, Nagpal, and their colleagues created CdTe quantum dots with a bandgap of 2.4 eV (517 nm). They used simple solution chemistry in which they synthesized the quantum dots directly in aqueous media from NaHTe and CdCl2 at 98°C. “The cadmium telluride had just the redox potential that we were looking for,” Nagpal said.
When illuminated with light above 2.4 eV, the quantum dots donated photoexcited electrons, producing superoxide radicals that, in turn, caused side reactions that possibly generated peroxide, other oxygen radicals, and reactive oxidative species. Illuminated 2.4 eV CdTe quantum dots killed up to 92% of multidrug-resistant E. coli after eight hours. In other tests, the treatment killed 29% of multidrug-resistant Staphylococcus aureus (specifically methicillin-resistant Staphylococcus aureus, or MRSA), 59% of Klebsiella pneumoniae, and 56% of Salmonella typhimurium in culture.
The researchers conducted a number of different experiments to show that the reduction and oxidation potentials of the nanomaterial drive the photoexcited quantum dots’ bacteria-killing effect. They found that changing the size of the nanoparticles changed their bandgap, ultimately reducing their reduction potential and therapeutic effect. Additionally, increasing the light intensity increased the therapeutic effect, and using an anaerobic environment removed the therapeutic effect.
The team also found that they could cause the bacteria to proliferate by using CIS quantum dots, which have different potentials than CdTe. This effect could prove useful in improving cell growth in bioreactors, among other things.
A primary benefit of the quantum dots, Nagpal said, is how easy they are to modify and tailor, which is important considering how quickly pathogens evolve. “We have a moving target for these therapies,” he said. “We cannot assume that the strain that is dominant now is the one to conquer because [a different strain] could come in tomorrow that is the new dominant species.”
“This is very interesting work of potentially high value highlighting a great need we have today to identify materials that can kill antibiotic-resistant bacteria,” said Thomas Webster, a chemical engineer who runs the Webster Nanomedicine Laboratory at Northeastern University. “This study provides a convincing series of data on the versatility of the quantum dots developed to kill numerous strains of antibiotic-resistant bacteria when activated.”
But Webster, who was not involved in the study, is still concerned about the potential toxicity of the quantum dots. “Mammalian cell toxicity of the quantum dots was only tested against one cell line and a transformed cell line that is not an accurate representation of the numerous healthy cells in our body,” Webster said, adding that Cd and Te also have toxicity concerns that need to be monitored in future studies (the researchers used a low dose of CdTe to minimize its harmful effects).
“Moving forward, we are refining the design of our nanoparticles,” Chatterjee said. “We are trying to push the limit of how far can we go in designing new therapies and making nanoparticles safer.” Eventually, the team hopes to conduct clinical trials using these quantum dots.
