Photoactivated antibiotics to treat intracellular infection of bacteria.

Antibiotic resistance combined with pathogen internalization leads to debilitating infections. Here we test novel superoxide producing, stimuli-activated quantum dots (QDs), to treat an intracellular infection of Salmonella enterica serovar Typhimurium in an osteoblast precursor cell line. These QDs are precisely tuned to reduce dissolved oxygen to superoxide and kill bacteria upon stimulation (e.g., light). We show QDs provide tunable clearance at various multiplicities of infection and limited host cell toxicity by modulating their concentration and stimuli intensity, proving the efficacy of superoxide producing QDs for intracellular infection treatment and establishing a framework for further testing in different infection models.

Safety and Biodistribution of Nanoligomers Targeting the SARS-CoV-2 Genome for the Treatment of COVID-19.

As the world braces to enter its fourth year of the coronavirus disease 2019 (COVID-19) pandemic, the need for accessible and effective antiviral therapeutics continues to be felt globally. The recent surge of Omicron variant cases has demonstrated that vaccination and prevention alone cannot quell the spread of highly transmissible variants. A safe and nontoxic therapeutic with an adaptable design to respond to the emergence of new variants is critical for transitioning to the treatment of COVID-19 as an endemic disease. Here, we present a novel compound, called SBCoV202, that specifically and tightly binds the translation initiation site of RNA-dependent RNA polymerase within the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome, inhibiting viral replication. SBCoV202 is a Nanoligomer, a molecule that includes peptide nucleic acid sequences capable of binding viral RNA with single-base-pair specificity to accurately target the viral genome. The compound has been shown to be safe and nontoxic in mice, with favorable biodistribution, and has shown efficacy against SARS-CoV-2 in vitro. Safety and biodistribution were assessed using three separate administration methods, namely, intranasal, intravenous, and intraperitoneal. Safety studies showed the Nanoligomer caused no outward distress, immunogenicity, or organ tissue damage, measured through observation of behavior and body weight, serum levels of cytokines, and histopathology of fixed tissue, respectively. SBCoV202 was evenly biodistributed throughout the body, with most tissues measuring Nanoligomer concentrations well above the compound KD of 3.37 nM. In addition to favorable availability to organs such as the lungs, lymph nodes, liver, and spleen, the compound circulated through the blood and was rapidly cleared through the renal and urinary systems. The favorable biodistribution and lack of immunogenicity and toxicity set Nanoligomers apart from other antisense therapies, while the adaptability of the nucleic acid sequence of Nanoligomers provides a defense against future emergence of drug resistance, making these molecules an attractive potential treatment for COVID-19.

Nanoligomers Targeting Human miRNA for the Treatment of Severe COVID-19 Are Safe and Nontoxic in Mice.

The devastating effects of the coronavirus disease 2019 (COVID-19) pandemic have made clear a global necessity for antiviral strategies. Most fatalities associated with infection from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) result at least partially from uncontrolled host immune response. Here, we use an antisense compound targeting a previously identified microRNA (miRNA) linked to severe cases of COVID-19. The compound binds specifically to the miRNA in question, miR-2392, which is produced by human cells in several disease states. The safety and biodistribution of this compound were tested in a mouse model via intranasal, intraperitoneal, and intravenous administration. The compound did not cause any toxic responses in mice based on measured parameters, including body weight, serum biomarkers for inflammation, and organ histopathology. No immunogenicity from the compound was observed with any administration route. Intranasal administration resulted in excellent and rapid biodistribution to the lungs, the main site of infection for SARS-CoV-2. Pharmacokinetic and biodistribution studies reveal delivery to different organs, including lungs, liver, kidneys, and spleen. The compound was largely cleared through the kidneys and excreted via the urine, with no accumulation observed in first-pass organs. The compound is concluded to be a safe potential antiviral treatment for COVID-19.

Photoactivated Indium Phosphide Quantum Dots Treat Multidrug-Resistant Bacterial Abscesses In Vivo.

The increasing prevalence of drug-resistant bacterial strains is causing illness and death in an unprecedented number of people around the globe. Currently implemented small-molecule antibiotics are both increasingly less efficacious and perpetuating the evolution of resistance. Here, we propose a new treatment for drug-resistant bacterial infection in the form of indium phosphide quantum dots (InP QDs), semiconductor nanoparticles that are activated by light to produce superoxide. We show that the superoxide generated by InP QDs is able to effectively kill drug-resistant bacteria in vivo to reduce subcutaneous abscess infection in mice without being toxic to the animal. Our InP QDs are activated by near-infrared wavelengths with high transmission through skin and tissues and are composed of biocompatible materials. Body weight and organ tissue histology show that the QDs are nontoxic at a macroscale. Inflammation and oxidative stress markers in serum demonstrate that the InP QD treatment did not result in measurable effects on mouse health at concentrations that reduce drug-resistant bacterial viability in subcutaneous abscesses. The InP QD treatment decreased bacterial viability by over 3 orders of magnitude in subcutaneous abscesses formed in mice. These InP QDs thus provide a promising alternative to traditional small-molecule antibiotics, with the potential to be applied to a wide variety of infection types, including wound, respiratory, and urinary tract infections.

Photoexcited Quantum Dots as Efficacious and Nontoxic Antibiotics in an Animal Model.

Drug-resistant bacterial infections are a growing cause of illness and death globally. Current methods of treatment are not only proving less effective but also perpetuate evolution of new resistance. Here we propose, through an in vivo model, a new treatment for drug-resistant bacterial infection that uses semiconductor nanoparticles, called quantum dots (QDs), that can be activated by light to produce superoxide to specifically and effectively kill drug-resistant bacteria. We adapt this technology for in vivo assessment of toxicity and treatment of a subcutaneous infection in mice. As our cadmium telluride QDs with 2.4 eV band gap (CdTe-2.4 QDs) are activated by blue light, we engineered LED patches to adhere to the infection site on mice, thus providing the light necessary for the activity of injected QDs and treatment of the infection. We show, through assessment of body weight, histology, and inflammation and oxidative stress markers in serum, that the CdTe-2.4 QDs are nontoxic at concentrations that reduce drug-resistant bacterial viability in subcutaneous abscesses. Further, CdTe-2.4 QDs did not accumulate in the body and were safely excreted in urine via renal clearance. CdTe-2.4 QD treatment decreased abscess viability by as much as 7 orders of magnitude. We thus propose an alternative treatment approach for drug-resistant topical infections: the injection of a low concentration of QDs and the application of an adhesive patch comprising only an LED and a battery. This treatment could revolutionize last-resort treatments of burn wounds, cellulitis, and other skin infections.