Hydrogen-Bonding-Regulated Morphology Control and the Impact on the Antibacterial Activity of Cationic π-Amphiphiles.

This manuscript describes the synthesis, self-assembly, and antibacterial properties of naphthalene-diimide (NDI)-derived cationic π-amphiphiles. Three such asymmetric NDI derivatives with a nonionic hydrophilic wedge and a guanidine group in the two opposite sides of the NDI chromophore were considered. They differ by a single functional group (hydrazide, amide, and ester for NDI-1, NDI-2, and NDI-3, respectively), located in the linker between the NDI and the hydrophilic wedge. For NDI-1, the H-bonding among the hydrazides regulated unilateral stacking and a preferential direction of curvature of the resulting supramolecular polymer, producing an unsymmetric polymersome with the guanidinium groups displayed at the outer surface. NDI-3, lacking any H-bonding group, exhibits π-stacking without any preferential orientation and generates spherical particles with a relatively poor display of the guanidium groups. In sharp contrast to NDI-1, NDI-2 exhibits an entangled one-dimensional (1D) fibrillar morphology, indicating the prominent role of the H-bonding motif of the amide group and flexibility of the linker. The antibacterial activity of these assemblies was probed against Staphylococcus aureus (Gram-positive) and Escherichia coli (Gram-negative). NDI-1 showed the most promising antibacterial activity with a minimum inhibitory concentration (MIC) of ∼7.8 µg/mL against S. aureus and moderate activity (MIC ∼ 125 µg/mL) against E. coli. In sharp contrast, NDI-3 did not show any significant activity against the bacteria, suggesting a strong impact of the H-bonding-regulated directional assembly. NDI-2, forming a fibrillar network, showed moderate activity against S. aureus and negligible activity against E. coli, highlighting a significant impact of the morphology. All of these three molecules were found to be compatible with mammalian cells from the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide (MTT) and hemolysis assay. The mechanistic investigation by membrane polarization assay, live/dead fluorescence assay, and microscopy studies confirmed the membrane disruption mechanism of cell killing for the lead candidate NDI-1.

Social and cultural determinants of antibiotics prescriptions: analysis from a public community health centre in North India.

This paper explores the socio cultural and institutional determinants of irresponsible prescription and use of antibiotics which has implications for the rise and spread of antimicrobial resistance (AMR). This study describes the patterns of prescription of antibiotics in a public facility in India and identifies the underlying institutional, cultural and social determinants driving the irresponsible use of antibiotics. The analysis is based on an empirical investigation of patients' prescriptions that reach the in-house pharmacy following an outpatient department (OPD) encounter with the clinician. The prescription analysis describes the factors associated with use of broad-spectrum antibiotics, and a high percentage of prescriptions for dental outpatient department prescribed as a precautionary measure. This paper further highlights the need for future research insights in combining socio-cultural approach with medical rationalities, to further explore questions our analysis highlights like higher antibiotic prescription, etc., Along with the recommendations for further research.

Mitochondrial Reactive Oxygen Species in Infection and Immunity.

Reactive oxygen species (ROS) contain at least one oxygen atom and one or more unpaired electrons and include singlet oxygen, superoxide anion radical, hydroxyl radical, hydroperoxyl radical, and free nitrogen radicals. Intracellular ROS can be formed as a consequence of several factors, including ultra-violet (UV) radiation, electron leakage during aerobic respiration, inflammatory responses mediated by macrophages, and other external stimuli or stress. The enhanced production of ROS is termed oxidative stress and this leads to cellular damage, such as protein carbonylation, lipid peroxidation, deoxyribonucleic acid (DNA) damage, and base modifications. This damage may manifest in various pathological states, including ageing, cancer, neurological diseases, and metabolic disorders like diabetes. On the other hand, the optimum levels of ROS have been implicated in the regulation of many important physiological processes. For example, the ROS generated in the mitochondria (mitochondrial ROS or mt-ROS), as a byproduct of the electron transport chain (ETC), participate in a plethora of physiological functions, which include ageing, cell growth, cell proliferation, and immune response and regulation. In this current review, we will focus on the mechanisms by which mt-ROS regulate different pathways of host immune responses in the context of infection by bacteria, protozoan parasites, viruses, and fungi. We will also discuss how these pathogens, in turn, modulate mt-ROS to evade host immunity. We will conclude by briefly giving an overview of the potential therapeutic approaches involving mt-ROS in infectious diseases.

Power Relations in Optimisation of Therapies and Equity in Access to Antibiotics (PROTEA) Study: investigating the intersection of socio-economic and cultural drivers on antimicrobial resistance (AMR) and its influence on healthcare access and health-providing behaviours in India and South Africa.

Across social structures within society, including healthcare, power relations manifest according to gender, socioeconomic status, race, ethnicity, and class influencing infection related healthcare access and health providing-behaviours. Therefore, accounting for sociocultural drivers, including gender, race, and class, and their influence on economic status can improve healthcare access and health-providing behaviours in infection prevention and control (IPC) as well as antibiotic use, which in turn helps mitigate the spread of antimicrobial resistance (AMR). This Wellcome funded research will investigate how and why the social determinants of health and economic status influence how people seek, experience, and provide healthcare for suspected or proven (bacterial) infections and how these factors influence antibiotic prescribing and use in South Africa (upper middle-income country) and India (lower middle-income country). The aim of this body of work is to, (1) define and estimate the sociocultural and economic drivers for AMR in different resource settings, (2) design, implement and evaluate context-sensitive IPC and antimicrobial stewardship (AMS) interventions, and (3) inform policy and strategy for AMR mitigation. The population will be healthcare workers (HCWs), patients, and their carers across acute medical and surgical pathways where IPC and antibiotic-related healthcare access and health-providing behaviours will be studied. Qualitative methods will include ethnographic research, semi-structured in-depth interviews, and focus groups with healthcare providers, patients and carers. Quantitative analysis of bedside observational data from hospitals and population level data on antibiotic use will study the various predictors of AMR using bivariable and multivariable regression analyses. The research will provide high-quality evidence on how social determinants intersect with health, social well-being, and vulnerability in IPC practices and antibiotic use. Using this knowledge we will: 1) design, implement, and measure effects of interventions accounting for these factors; 2) provide a toolkit for advocacy for actors in AMR, and healthcare to assist them to promote dialogue, including policy dialogue on this issue. This work directly benefits the target population and informs healthcare services and practice across the participating countries with potential for wider translation. The setting will be hospitals in South Africa (middle-income country) and India (lower middle-income country). The population will be healthcare workers (HCWs), patients, and their carers across acute medical and surgical pathways where IPC and antibiotic-related health-seeking and health-providing behaviours will be studied. These populations represent communities most affected by infections and AMR because existing interventions do not address a) differences in how surgical versus medical teams manage infections; b) the role of the wider social network of individuals on their decision-making, c) intersection of the social determinants of health including race, gender, socioeconomic deprivation with AMR.

Systems thinking based approaches to engage with health inequities shaping Antimicrobial Resistance in low and lower-middle-income countries.

This paper argues for 'systems thinking' as a conceptual framework to address antimicrobial resistance, especially focusing on the context of low and lower middle-income countries (LLMICs), which are plagued with health inequities that magnify the AMR threat. Systems thinking provides two avenues to enhance these mitigation efforts: i) it helps go beyond a purely biomedical approach to incorporate considerations of the social and informational; ii) particularly relevant as is it helps to understand the role of health inequities in shaping AMR related prevention and care processes.

Microfoundations of Data-Driven Antimicrobial Stewardship Policy (ASP).

This paper introduces a comprehensive framework that elucidates the microfoundations of data-driven antimicrobial stewardship programs (ASPs), specifically focusing on resource-constrained settings. Such settings necessitate the utilization of available resources and engagement among multiple stakeholders. The microfoundations are conceptualized as interlinked components: input, process, output, and outcome. Collectively, these components provide a comprehensive framework for understanding the development and implementation of data-driven ASPs in resource-constrained settings. It underscores the importance of considering both the social and material dimensions when evaluating microbiological, clinical, and social impacts. By harmonizing technology, practices, values, and behaviors, this framework offers valuable insights for the development, implementation, and assessment of ASPs tailored to resource-constrained environments.

"A living lab within a lab": approaches and challenges for scaling digital public health in resource-constrained settings.

A living lab is an emerging concept, particularly in Europe, as a vehicle to develop digital innovations through a process of co-produced design and development, which takes place, physically and socially, in real-life use contexts. However, there is limited research relating to guiding our understanding of the process by which such labs are established, and digital innovations are co-created and scaled to other settings requiring similar solutions. Furthermore, beyond Europe, the concept of a living lab has not found widespread application in low- and middle-income countries (LMICs), particularly in their public health contexts. Public health systems offer the unique scaling challenge of "all or nothing", implying that data are required from the whole population rather than isolated pilot settings. The living lab approach promises the rich potential to strengthen public systems but comes with twin interconnected challenges. First, for building appropriate digital solutions to address local public health challenges, and second, in scaling them to other public health facilities. This article investigates these twin challenges through ongoing empirical work in India and identifies three key domains of analysis, which are as follows: the first concerns the process of establishing an enabling structure of a "living lab within a lab"; the second concerns leveraging the capabilities offered by free and open-source digital technologies; and the third concerns the driving impetus to scaling through agile and co-constructed technical support.

Deciphering the enigmatic crosstalk between prostate cancer and Alzheimer's disease: A current update on molecular mechanisms and combination therapy.

Alzheimer's disease (AD) and prostate cancer (PCa) are considered the leading causes of death in elderly people worldwide. Although both these diseases have striking differences in their pathologies, a few underlying mechanisms are similar when cell survival is considered. In the current study, we employed an in-silico approach to decipher the possible role of bacterial proteins in the initiation and progression of AD and PCa. We further analyzed the molecular connections between these two life-threatening diseases. The androgen deprivation therapy used against PCa has been shown to promote castrate resistant PCa as well as AD. In addition, cell signaling pathways, such as Akt, IGF, and Wnt contribute to the progression of both AD and PCa. Besides, various proteins and genes are also common in disease progression. One such similarity is mTOR signaling. mTOR is the common downstream target for many signaling pathways and plays a vital role in both PCa and AD. Targeting mTOR can be a favorable line of treatment for both AD and PCa. However, drug resistance is one of the challenges in effective drug therapy. A few drugs that target mTOR have now become ineffective due to the development of resistance. In that regard, phytochemicals can be a rich source of novel drug candidates as they can act via multiple mechanisms. This review also presents mTOR targeting phytochemicals with promising anti-PCa, anti-AD activities, and approaches to overcome the issues associated with phytochemical-based therapies in clinical trials.

Facial selectivities in the nucleophilic additions of 2,3-unsaturated 3-arylsulfinyl pyranosides.

2,3-Unsaturated 3-arylsulfinyl pyranosides undergo nucleophilic additions at C-2, with facial selectivities depending on the nucleophile and the substituent on sulfinyl sulfur. The reactions of such sugar vinyl sulfoxides lead to the addition of nucleophile preferring an axial orientation at C-2, with concomitant formation of an allylic bond at C-3 to C-4. This trend in the addition pattern is observed for primary amine, carbon and sulfur nucleophiles, whereas secondary amines prefer an equatorial addition at C-2. The effect of p-tolylthio- versus (p-isopropylphenyl)thio vinyl sulfoxide is that the equatorial nucleophilic addition is preferred even more with the latter vinyl sulfoxide.

Reactivity switching and selective activation of C-1 or C-3 in 2,3-unsaturated thioglycosides.

Reactivity switching and selective activation of C-1 or C-3 in 2,3-unsaturated thioglycosides, namely, 2,3-dideoxy-1-thio-D-hex-2-enopyranosides are reported. The reactivity switching allowed activation of either C-1 or C-3, with the use of either N-iodosuccinimide (NIS)/triflic acid (TfOH) or TfOH alone. C-1 glycosylation with alcohol acceptors occurred in the presence of NIS/TfOH, without the acceptors reacting at C-3. On the other hand, reaction of 2,3-unsaturated thioglycosides with alcohols mediated by triflic acid led to transposition of C-1 ethylthio-moiety to C-3 intramolecularly, to form 3-ethylthio-glycals. Resulting glycals underwent glycosylation with alcohols to afford 3-ethylthio-2-deoxy glycosides. However, when thiol was used as an acceptor, only a stereoselective addition at C-3 resulted, so as to form C-1, C-3 dithio-substituted 2-deoxypyranosides.