Polymeric nanobiotics as a novel treatment for mycobacterial infections.

Mycobacterium tuberculosis (Mtb) remains a major challenge to global health, made worse by the spread of multi-drug resistance. Currently, the efficacy and safety of treatment is limited by difficulties in achieving and sustaining adequate tissue antibiotic concentrations while limiting systemic drug exposure to tolerable levels. Here we show that nanoparticles generated from a polymer-antibiotic conjugate ('nanobiotics') deliver sustained release of active drug upon hydrolysis in acidic environments, found within Mtb-infected macrophages and granulomas, and can, by encapsulation of a second antibiotic, provide a mechanism of synchronous drug delivery. Nanobiotics are avidly taken up by infected macrophages, enhance killing of intracellular Mtb, and are efficiently delivered to granulomas and extracellular mycobacterial cords in vivo in an infected zebrafish model. We demonstrate that isoniazid (INH)-derived nanobiotics, alone or with additional encapsulation of clofazimine (CFZ), enhance killing of mycobacteria in vitro and in infected zebrafish, supporting the use of nanobiotics for Mtb therapy and indicating that nanoparticles generated from polymer-small molecule conjugates might provide a more general solution to delivering co-ordinated combination chemotherapy.Rosetrees Trust Interdisciplinary Prize 2015 Wellcome Trust awards 107032/Z/15/Z and 10/H0305/55 NIHR Cambridge Biomedical Research Centre Award MRC AMR Theme award MR/N02995X/1 Marie-Curie IF CFZEBRA 75197

Overview of nanotherapeutics for bacterial infections

The rapid emergence of antibiotic-resistant bacteria poses one of the greatest threats to public health as conventional therapies and commercial antibiotics are dropping their effectiveness. In the race for the discovery of new strategies to prevent a scenario in which commonplace infections prove fatal, nanomaterials stand in the limelight due to their unique physicochemical properties that can be seized to overcome common resistance mechanisms. Nanoparticle-driven drug delivery emerges as a beacon of hope, shielding antibiotics from enzymatic degradation, enhancing their targeted delivery to afflicted sites in therapeutically potent concentrations, and minimising undesired side effects. Drugs can either be entrapped or chemically conjugated to nanoparticles, with the latter offering a myriad of possibilities in orchestrating spatiotemporal controlled release of the therapeutic payload. Meanwhile, nanomaterials can also display intrinsic antimicrobial properties, either by direct disruption of bacterial cell membranes (e.g., nanoparticles functionalised with cationic groups) or by instigating the generation of ROS (e.g., metallic nanoparticles). The clinical implementation of nanotherapeutics still faces considerable challenges, mainly related with their complex chemistry and polydispersity, which poses difficulties related to cost-effectiveness, scale-up, and Chemistry, Manufacturing, and Controls (CMC) management. Still, the development of computational approaches allowing a better understanding of nano-bio interactions and predictive biodistribution, pharmacokinetics, and toxicology, along with a harmonised international regulatory framework, is expected to facilitate clinical translation in the near future

Robust rapid-setting antibacterial liquid bandages

Abstract: Bandaging is a steadfast but time-consuming component of wound care with limited technical advancements to date. Bandages must be changed and infection risk managed. Rapid-set liquid bandages are efficient alternatives but lack durability or inherent infection control. We show here that antibacterial zinc (Zn) and copper (Cu) species greatly enhance the barrier properties of the natural, waterproof, bio-adhesive polymer, shellac. The material demonstrated marked antibacterial contact properties and, in ex-vivo studies, effectively locked-in pre-applied therapeutics. When challenged in vivo with the polybacterial bovine wound infection ‘digital dermatitis’, Zn/Cu-shellac adhered rapidly and robustly over pre-applied antibiotic. The bandage self-degraded, appropriately, over 7 days despite extreme conditions (faecal slurry). Treatment was well-tolerated and clinical improvement was observed in animal mobility. This new class of bandage has promise for challenging topical situations in humans and other animals, especially away from controlled, sterile clinical settings where wounds urgently require protection from environmental and bacterial contamination

Situational factors shape moral judgments in the trolley dilemma in Eastern, Southern, and Western countries in a culturally diverse sample

Much research on moral judgment is centered on moral dilemmas in which deontological perspectives (i.e., emphasizing rules, individual rights and duties) are in conflict with utilitarian judgements (i.e., following the greater good defined through consequences). A central finding of this field Greene et al. showed that psychological and situational factors (e.g., the intent of the agent, or physical contact between the agent and the victim) play an important role in people’s use of deontological versus utilitarian considerations when making moral decisions. As their study was conducted with US samples, our knowledge is limited concerning the universality of this effect, in general, and the impact of culture on the situational and psychological factors of moral judgments, in particular. Here, we empirically test the universality of deontological and utilitarian judgments by replicating Greene et al.’s experiments on a large (N = X,XXX) and diverse (WEIRD and non-WEIRD) sample across the world to explore the influence of culture on moral judgment. The relevance of this exploration to a broad range of policy-making problems is discussed

Situational factors shape moral judgements in the trolley dilemma in Eastern, Southern and Western countries in a culturally diverse sample.

From PubMed via Jisc Publications RouterHistory: received 2019-04-15, accepted 2022-02-14Publication status: aheadofprintThe study of moral judgements often centres on moral dilemmas in which options consistent with deontological perspectives (that is, emphasizing rules, individual rights and duties) are in conflict with options consistent with utilitarian judgements (that is, following the greater good based on consequences). Greene et al. (2009) showed that psychological and situational factors (for example, the intent of the agent or the presence of physical contact between the agent and the victim) can play an important role in moral dilemma judgements (for example, the trolley problem). Our knowledge is limited concerning both the universality of these effects outside the United States and the impact of culture on the situational and psychological factors affecting moral judgements. Thus, we empirically tested the universality of the effects of intent and personal force on moral dilemma judgements by replicating the experiments of Greene et al. in 45 countries from all inhabited continents. We found that personal force and its interaction with intention exert influence on moral judgements in the US and Western cultural clusters, replicating and expanding the original findings. Moreover, the personal force effect was present in all cultural clusters, suggesting it is culturally universal. The evidence for the cultural universality of the interaction effect was inconclusive in the Eastern and Southern cultural clusters (depending on exclusion criteria). We found no strong association between collectivism/individualism and moral dilemma judgements. [Abstract copyright: © 2022. The Author(s), under exclusive licence to Springer Nature Limited.

Situational factors shape moral judgements in the trolley dilemma in Eastern, Southern and Western countries in a culturally diverse sample

The study of moral judgements often centres on moral dilemmas in which options consistent with deontological perspectives (that is, emphasizing rules, individual rights and duties) are in conflict with options consistent with utilitarian judgements (that is, following the greater good based on consequences). Greene et al. (2009) showed that psychological and situational factors (for example, the intent of the agent or the presence of physical contact between the agent and the victim) can play an important role in moral dilemma judgements (for example, the trolley problem). Our knowledge is limited concerning both the universality of these effects outside the United States and the impact of culture on the situational and psychological factors affecting moral judgements. Thus, we empirically tested the universality of the effects of intent and personal force on moral dilemma judgements by replicating the experiments of Greene et al. in 45 countries from all inhabited continents. We found that personal force and its interaction with intention exert influence on moral judgements in the US and Western cultural clusters, replicating and expanding the original findings. Moreover, the personal force effect was present in all cultural clusters, suggesting it is culturally universal. The evidence for the cultural universality of the interaction effect was inconclusive in the Eastern and Southern cultural clusters (depending on exclusion criteria). We found no strong association between collectivism/individualism and moral dilemma judgements

Publisher correction: Situational factors shape moral judgements in the trolley dilemma in Eastern, Southern and Western countries in a culturally diverse sample

Correction to: Nature Human Behaviour https://doi.org/10.1038/s41562-022-01319-5, published online 14 April 2022