(660d) Novel Approaches to Treatment of Infectious Disease Using Quantum Dots and Nucleic Acid Therapeutics

Infectious disease remains a major threat to public health, despite strides made in the past century for the treatment of both bacterial and viral infection. The rise of drug-resistant bacterial infections and the COVID-19 pandemic have demonstrated the dire need for new treatment strategies against infectious disease. COVID-19 has caused 602,000 deaths in the United States, while antibiotic-resistant bacteria are predicted to cause ten million deaths annually worldwide by 2050, more than all cancers combined, unless significant strides are made in treatment options. Meanwhile, pharmaceutical companies must devote ten to twenty years to develop a single drug for a single ailment. Yet bacteria and viruses are quick to adapt. Resistant bacterial strains appear within only a couple years of the release of a new antibiotic, while antiviral options remain severely limited. Our antibiotic and antiviral discovery pipelines must accommodate the necessary shift away from traditional small molecule therapies toward more robust and adaptive drugs.

Here, we investigate new ways of combating resistant bacteria and newly arising viruses and applying those methods in vivo to optimize them for clinical use. We present two novel methods: antibiotic photoactivated semiconductor nanoparticles called quantum dots (QDs) and antivirals from Sachi Bioworks’ proprietary synthetic nucleic acid-based drug discovery platform. Photoactivated QDs kill bacteria by producing superoxide, which targets iron clusters in bacterial cells, and additionally have been shown to potentiate the activity of antibiotics against resistant bacteria. Our QDs show great promise as a novel antimicrobial therapy. Indium phosphide (InP) QDs injected subcutaneously into mice caused no measured toxicity to the host animal after six consecutive days of treatment. InP QDs are activated by near-infrared (NIR) light, which was provided to the injection site using high-intensity LEDs. We then used InP QDs to treat subcutaneous abscesses of human clinical isolate Escherichia coli in mice. As NIR light has high transmittance through skin and tissue, QDs injected under the skin were sufficiently activated for bacterial killing. We observed decreased bacterial count by QD dosages of 2 and 4 μM compared to PBS treatment. A 6000-fold drop in abscess bacterial viability was observed in mice treated with 4 μM QDs compared to PBS control.

The antivirals bind to specific DNA or mRNA sequences and offer high specificity and superior transport into cells. These molecules target the SARS-CoV-2 genome, as well as a host factor. These antivirals were assessed for toxicity in mice using both intravenous and intranasal administration, as intranasal drug administration maximizes treatment concentration at the respiratory infection site. Preliminary data shows a favorable safety profile in our murine model.

These novel approaches to treatment of infectious disease could provide necessary alternatives to small-molecule drugs. The QDs offer a new method of using superoxide to kill bacteria, including bacteria that have developed resistance to small-molecule drugs. The antivirals presented are highly adaptable and the sequence may be adjusted to target new variants of respiratory viruses. These novel therapies are an important new step in managing new drug-resistant bacterial strains and deadly viruses.