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Proliferation of multidrug-resistant (MDR) bacteria poses a threat to human health, requiring new strategies. Here we propose using fitness neutral gene expression perturbations to potentiate antibiotics. We systematically explored 270 gene knockout-antibiotic combinations inEscherichia coli, identifying 90 synergistic interactions. Identified gene targets were subsequently tested for antibiotic synergy on the transcriptomic level via multiplexed CRISPR-dCas9 and showed successful sensitization ofE. coliwithout a separate fitness cost. These fitness neutral gene perturbations worked as co-therapies in reducing aSalmonella entericaintracellular infection in HeLa. Finally, these results informed the design of four antisense peptide nucleic acid (PNA) co-therapies,csgD,fnr,recAandacrA, against four MDR, clinically isolated bacteria. PNA combined with sub-minimal inhibitory concentrations of trimethoprim against two isolates ofKlebsiella pneumoniaeandE. colishowed three cases of re-sensitization with minimal fitness impacts. Our results highlight a promising approach for extending the utility of current antibiotics.

Enzymatic Fisher‐Tropsch (FT) process catalyzed by vanadium (V)‐nitrogenase can convert carbon monoxide (CO) to longer‐chain hydrocarbons (>C2) under ambient conditions, although this process requires high‐cost reducing agent(s) and/or the ATP‐dependent reductase as electron and energy sources. Using visible light‐activated CdS@ZnS (CZS) core‐shell quantum dots (QDs) as alternative reducing equivalent for the catalytic component (VFe protein) of V‐nitrogenase, we first report a CZS : VFe biohybrid system that enables effective photo‐enzymatic C−C coupling reactions, hydrogenating CO into hydrocarbon fuels (up to C4) that can be hardly achieved with conventional inorganic photocatalysts. Surface ligand engineering optimizes molecular and opto‐electronic coupling between QDs and the VFe protein, realizing high efficiency (internal quantum yield >56 %), ATP‐independent, photon‐to‐fuel production, achieving an electron turnover number of >900, that is 72 % compared to the natural ATP‐coupled transformation of CO into hydrocarbons by V‐nitrogenase. The selectivity of products can be controlled by irradiation conditions, with higher photon flux favoring (longer‐chain) hydrocarbon generation. The CZS : VFe biohybrids not only can find applications in industrial CO removal for high‐value‐added chemical production by using the cheap, renewable solar energy, but also will inspire related research interests in understanding the molecular and electronic processes in photo‐biocatalytic systems.

Multidrug-resistant (MDR) bacteria pose a grave concern to global health, which is perpetuated by a lack of new treatments and countermeasure platforms to combat outbreaks or antibiotic resistance. To address this, we have developed a Facile Accelerated Specific Therapeutic (FAST) platform that can develop effective peptide nucleic acid (PNA) therapies against MDR bacteria within a week. Our FAST platform uses a bioinformatics toolbox to design sequence-specific PNAs targeting non-traditional pathways/genes of bacteria, then performs in-situ synthesis, validation, and efficacy testing of selected PNAs. As a proof of concept, these PNAs were tested against five MDR clinical isolates: carbapenem-resistantEscherichia coli, extended-spectrum beta-lactamaseKlebsiella pneumoniae, New Delhi Metallo-beta-lactamase-1 carryingKlebsiella pneumoniae, and MDRSalmonella enterica. PNAs showed significant growth inhibition for 82% of treatments, with nearly 18% of treatments leading to greater than 97% decrease. Further, these PNAs are capable of potentiating antibiotic activity in the clinical isolates despite presence of cognate resistance genes. Finally, the FAST platform offers a novel delivery approach to overcome limited transport of PNAs into mammalian cells by repurposing the bacterial Type III secretion system in conjunction with a kill switch that is effective at eliminating 99.6% of an intracellularSalmonellainfection in human epithelial cells.

The emergence of multidrug‐resistant (MDR) pathogens represents one of the most urgent global public health crises. Light‐activated quantum dots (QDs) are alternative antimicrobials, with efficient transport, low cost, and therapeutic efficacy, and they can act as antibiotic potentiators, with a mechanism of action orthogonal to small‐molecule drugs. Furthermore, light‐activation enhances control over the spatiotemporal release and dose of the therapeutic superoxide radicals from QDs. However, the limited deep‐tissue penetration of visible light needed for QD activation, and concern over trace heavy metals, have prevented further translation. Herein, we report two indium phosphide (InP) QDs that operate in the near‐infrared and deep‐red light window, enabling deeper tissue penetration. These heavy‐metal‐free QDs eliminate MDR pathogenic bacteria, while remaining non‐toxic to host human cells. This work provides a pathway for advancing QD nanotherapeutics to combat MDR superbugs.

The emergence of multidrug‐resistant (MDR) pathogens represents one of the most urgent global public health crises. Light‐activated quantum dots (QDs) are alternative antimicrobials, with efficient transport, low cost, and therapeutic efficacy, and they can act as antibiotic potentiators, with a mechanism of action orthogonal to small‐molecule drugs. Furthermore, light‐activation enhances control over the spatiotemporal release and dose of the therapeutic superoxide radicals from QDs. However, the limited deep‐tissue penetration of visible light needed for QD activation, and concern over trace heavy metals, have prevented further translation. Herein, we report two indium phosphide (InP) QDs that operate in the near‐infrared and deep‐red light window, enabling deeper tissue penetration. These heavy‐metal‐free QDs eliminate MDR pathogenic bacteria, while remaining non‐toxic to host human cells. This work provides a pathway for advancing QD nanotherapeutics to combat MDR superbugs.