Abstract
The rapid emergence of superbugs, or multi-drug resistant (MDR) organisms, has prompted a search for novel antibiotics, beyond traditional small-molecule therapies. Nanotherapeutics are being investigated as alternatives, and recently superoxide-generating quantum dots (QDs) have been shown as important candidates for selective light-activated therapy, while also potentiating existing antibiotics against MDR superbugs. Their therapeutic action is selective, can be tailored by simply changing their quantum-confined conduction-valence band (CB-VB) positions and alignment with different redox half-reactions—and hence their ability to generate specific radical species in biological media. Here, we show the design of superoxide-generating QDs using optimal QD material and size well-matched to superoxide redox potential, charged ligands to modulate their uptake in cells and selective redox interventions, and core/shell structures to improve their stability for therapeutic action. We show that cadmium telluride (CdTe) QDs with conduction band (CB) position at −0.5 V with respect to Normal Hydrogen Electron (NHE) and visible 2.4 eV bandgap generate a large flux of selective superoxide radicals, thereby demonstrating the effective light-activated therapy. Although the positively charged QDs demonstrate large cellular uptake, they bind indiscriminately to cell surfaces and cause non-selective cell death, while negatively charged and zwitterionic QD ligands reduce the uptake and allow selective therapeutic action via interaction with redox species. The stability of designed QDs in biologically-relevant media increases with the formation of core-shell QD structures, but an appropriate design of core-shell structures is needed to minimize any reduction in charge injection efficiency to adsorbed oxygen molecules (to form superoxide) and maintain similar quantitative generation of tailored redox species, as measured using electron paramagnetic resonance (EPR) spectroscopy and electrochemical impedance spectroscopy (EIS). Using these findings, we demonstrate the rational design of QDs as selective therapeutic to kill more than 99% of a priority class I pathogen, thus providing an effective therapy against MDR superbugs.
Highlights
Antibiotics have been a cornerstone of modern medicine, where molecules like β-lactams are an important and frequently used class
For the specific class of superoxide-generating therapeutic against multi-drug resistant (MDR) superbugs, we developed cadmium telluride (CdTe) nanoparticles with a band gap of 2.4 eV (CdTe2.4)—corresponding to a diameter of 2.7–3.0 nm (Figure 1A)
We investigated the therapeutic efficacy of these stability-enhanced CdTe/Cd nanoparticles quantum dots (QDs) in countering a WHO priority I MDR Enterobacteriaceae Klebsiella pneumoniae expressing New Delhi metallo-beta-lactamase 1 (NDM-1), an enzyme that offers resistance to a broad range of beta-lactam antibiotics including last-resort antibiotics such as carbapenems
Summary
Antibiotics have been a cornerstone of modern medicine, where molecules like β-lactams are an important and frequently used class. Three different classes of light-activated nanoscale therapeutics have been proposed: metal-nanoparticle induced photothermal therapy (Hirsch et al, 2003; Connor et al, 2005; Huang et al, 2006), small photosensitizing molecules induced photodynamic therapy (Dai et al, 2010; Hamblin and Hasan, 2014), and quantum dot (QD)-based selective-redox (Courtney et al, 2016, 2017; Reynolds et al, 2017), therapies. While non-selective heating of surrounding medium and indiscriminate cell killing by metal nanoparticles reduces their suitability as an antibiotic, lack of tunability or control over the specific reactive oxygen species (ROS) generated by photodynamic therapies, such as nonselective singlet oxygen (Bonnett, 1995; Jarvi et al, 2006; Ma et al, 2008; Gomes et al, 2011; Hamblin and Hasan, 2014), reduces its appeal as a precision therapeutic approach. Superoxide-generating QDs have recently been shown as a two-pronged strategy for combating superbugs: first, as therapeutics to selectively eliminate MDR bacteria (Courtney et al, 2016), and second, by potentiating existing pipeline of antibiotics which are nominally ineffective against these potent pathogens (Courtney et al, 2017)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
