Fluorogenic Probes of the Mycobacterial Membrane as Reporters of Antibiotic Action.

The genus Mycobacterium includes species such as Mycobacterium tuberculosis, which can cause deadly human diseases. These bacteria have a protective cell envelope that can be remodeled to facilitate their survival in challenging conditions. Understanding how such conditions affect membrane remodeling can facilitate antibiotic discovery and treatment. To this end, we describe an optimized fluorogenic probe, N-QTF, that reports on mycolyltransferase activity, which is vital for cell division and remodeling. N-QTF is a glycolipid probe that can reveal dynamic changes in the mycobacterial cell envelope in both fast- and slow-growing mycobacterial species. Using this probe to monitor the consequences of antibiotic treatment uncovered distinct cellular phenotypes. Even antibiotics that do not directly inhibit cell envelope biosynthesis cause conspicuous phenotypes. For instance, mycobacteria exposed to the RNA polymerase inhibitor rifampicin release fluorescent extracellular vesicles (EVs). While all mycobacteria release EVs, fluorescent EVs were detected only in the presence of RIF, indicating that exposure to the drug alters EV content. Macrophages exposed to the EVs derived from RIF-treated cells released lower levels of cytokines, suggesting the EVs moderate immune responses. These data suggest that antibiotics can alter EV content to impact immunity. Our ability to see such changes in EV constituents directly results from exploiting these chemical probes.

Inflammation unites diverse acute and chronic diseases.

BACKGROUND: Inflammation and immunity contribute pivotally to diverse acute and chronic diseases. Inflammatory pathways have become increasingly targets for therapy. Yet, despite substantial similarity in mechanisms and pathways, the scientific, medical, pharma and biotechnology sectors have generally focused programs finely on a single disease entity or organ system. This insularity may impede progress in innovation and the harnessing of powerful new insights into inflammation biology ripe for clinical translation. METHODS: A multidisciplinary thinktank reviewed highlights how inflammation contributes to diverse diseases, disturbed homeostasis, ageing and impaired healthspan. We explored how common inflammatory and immune mechanisms that operate in key conditions in their respective domains. This consensus review highlights the high degree of commonality of inflammatory mechanisms in a diverse array of conditions that together contribute a major part of the global burden of morbidity and mortality and present an enormous challenge to public health and drain on resources. RESULTS: We demonstrate how that shared inflammatory mechanisms unite many seemingly disparate diseases, both acute and chronic. The examples of infection, cardiovascular conditions, pulmonary diseases, rheumatological disorders, dementia, cancer and ageing illustrate the overlapping pathogenesis. We outline opportunities to synergize, reduce duplication and consolidate efforts of the clinical, research and pharmaceutical communities. Enhanced recognition of these commonalties should promote cross-fertilization and hasten progress in this rapidly moving domain. CONCLUSIONS: Greater appreciation of the shared mechanisms should simplify understanding seemingly disparate diseases for clinicians and help them to recognize inflammation as a therapeutic target which the development of novel therapies is rendering actionable.

Genetically encoded transcriptional plasticity underlies stress adaptation in Mycobacterium tuberculosis.

Transcriptional regulation is a critical adaptive mechanism that allows bacteria to respond to changing environments, yet the concept of transcriptional plasticity (TP) - the variability of gene expression in response to environmental changes - remains largely unexplored. In this study, we investigate the genome-wide TP profiles of Mycobacterium tuberculosis (Mtb) genes by analyzing 894 RNA sequencing samples derived from 73 different environmental conditions. Our data reveal that Mtb genes exhibit significant TP variation that correlates with gene function and gene essentiality. We also find that critical genetic features, such as gene length, GC content, and operon size independently impose constraints on TP, beyond trans-regulation. By extending our analysis to include two other Mycobacterium species -- M. smegmatis and M. abscessus -- we demonstrate a striking conservation of the TP landscape. This study provides a comprehensive understanding of the TP exhibited by mycobacteria genes, shedding light on this significant, yet understudied, genetic feature encoded in bacterial genomes.

Targeted protein degradation in mycobacteria uncovers antibacterial effects and potentiates antibiotic efficacy.

Proteolysis-targeting chimeras (PROTACs) represent a new therapeutic modality involving selectively directing disease-causing proteins for degradation through proteolytic systems. Our ability to exploit targeted protein degradation (TPD) for antibiotic development remains nascent due to our limited understanding of which bacterial proteins are amenable to a TPD strategy. Here, we use a genetic system to model chemically-induced proximity and degradation to screen essential proteins in Mycobacterium smegmatis (Msm), a model for the human pathogen M. tuberculosis (Mtb). By integrating experimental screening of 72 protein candidates and machine learning, we find that drug-induced proximity to the bacterial ClpC1P1P2 proteolytic complex leads to the degradation of many endogenous proteins, especially those with disordered termini. Additionally, TPD of essential Msm proteins inhibits bacterial growth and potentiates the effects of existing antimicrobial compounds. Together, our results provide biological principles to select and evaluate attractive targets for future Mtb PROTAC development, as both standalone antibiotics and potentiators of existing antibiotic efficacy.

Fossil-Fuel Pollution and Climate Change - A New NEJM Group Series.

Fossil-Fuel Pollution and Climate ChangeThe editors announce a new NEJM Group series on climate change and the increasingly urgent health and care delivery challenges we face. Articles will appear in the New England Journal of Medicine, in NEJM Evidence, and in NEJM Catalyst Innovations in Care Delivery.

Llamamiento a adoptar medidas urgentes para limitar los aumentos de temperatura en el mundo, restablecer la diversidad biológica y proteger la salud / Call for emergency action to limit global temperature increases, restore biodiversity, and protect health

La publicación de este artículo es una iniciativa organizada por la Alianza Global por el Clima y la Salud (GCHA, por sus siglas en inglés) a través de la Alianza de Salud del Reino Unido sobre el Cambio Climático (UKHACC, por sus siglas en inglés) y los miembros del Grupo de Trabajo Latinoamericano sobre Cambio Climático y Salud. La convocatoria tiene un doble objetivo: que los líderes mundiales acuerden los cambios necesarios para mantener el aumento de la temperatura global por debajo de 1,5°C y que los profesionales de la salud adquieran una mayor relevancia en el debate global sobre la crisis climática y la pérdida de la biodiversidad. La convocatoria se desarrolla en el contexto de la próxima celebración de la Asamblea General de Naciones Unidas que se iniciará el 14 de septiembre de 2021, así como también de la celebración de la conferencia climática COP26 que este año se realizará en Glasgow. Este artículo, cuya autoría pertenece principalmente a editores de 18 prestigiosas revistas científicas ampliamente representativas de los continentes y disciplinas de la salud del mundo, ya ha sido publicada simultáneamente en más de 200 revistas científicas internacionales (https://www.bmj.com/content/full-list-authors-and-signatories-climate-emergency-editorial-september-2021). En esta ocasión, la Revista Argentina de Salud Pública se suma a esta iniciativa conjunta a través de la publicación del artículo en español, con el fin de promover su difusión en los países de la Región. El editorial expresa también la necesidad de restablecer la diversidad biológica y proteger la salud, y de que los países de altos ingresos hagan mayores recortes en sus emisiones de carbono y transfieran fondos a los países de ingresos bajos y medianos. Además, exhorta a la intervención de los gobiernos en el rediseño de los sistemas de transporte, las ciudades, la producción y distribución de alimentos, los mercados para las inversiones financieras, los sistemas de salud, entre otros aspectos, lo que redundaría en amplios beneficios para la salud.