RESUMEN

Mycobacterium smegmatis (M.sm) is frequently used as an alternative model organism in Mycobacterium tuberculosis (M.tb) studies. While containing high sequence homology with M.tb, it is considered non-pathogenic in humans. As such it has been used to study M.tb and other infections in vivo and more recently been explored for potential therapeutic applications. A body of previous research has highlighted the potential of using genetically modified M.sm displaying rapid growth and unique immunostimulatory characteristics as an effective vaccine vector. Novel systems biology techniques can further serve to optimize these delivery constructs. In this article, we review recent advancements in vaccinomics tools that support the efficacy of a M.sm-based vaccine vector. Moreover, the integration of systems biology and molecular omics techniques in these pioneering studies heralds a potential accelerated pipeline for the development of next-generation recombinant vaccines against rapidly developing diseases.

RESUMEN

Several decades after the discovery of the first antibiotic (penicillin) microbes have evolved novel mechanisms of resistance; endangering not only our abilities to combat future bacterial pandemics but many other clinical challenges such as acquired infections during surgeries. Antimicrobial resistance (AMR) is attributed to the mismanagement and overuse of these medications and is complicated by a slower rate of the discovery of novel drugs and targets. Bacterial peptidoglycan (PG), a three-dimensional mesh of glycan units, is the foundation of the cell wall that protects bacteria against environmental insults. A significant percentage of drugs target PG, however, these have been rendered ineffective due to growing drug resistance. Identifying novel druggable targets is, therefore, imperative. Uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) is one of the key building blocks in PG production, biosynthesized by the bifunctional enzyme N-acetyl-glucosamine-1-phosphate uridyltransferase (GlmU). UDP-GlcNAc metabolism has been studied in many organisms, but it holds some distinctive features in bacteria, especially regarding the bacterial GlmU enzyme. In this review, we provide an overview of different steps in PG biogenesis, discuss the biochemistry of GlmU, and summarize the characteristic structural elements of bacterial GlmU vital to its catalytic function. Finally, we will discuss various studies on the development of GlmU inhibitors and their significance in aiding future drug discoveries.

Asunto(s)

Peptidoglicano , UDP-Glucosa-Hexosa-1-Fosfato Uridiltransferasa , Glucosamina/metabolismo , Fosfatos , Uridina Difosfato

RESUMEN

Metabolomics is emerging as a promising tool to understand the effect of immunometabolism for the development of novel host-directed alternative therapies. Immunometabolism can modulate both innate and adaptive immunity in response to pathogens and vaccinations. For instance, infections can affect lipid and amino acid metabolism while vaccines can trigger bile acid and carbohydrate pathways. Metabolomics as a vaccinomics tool, can provide a broader picture of vaccine-induced biochemical changes and pave a path to potentiate the vaccine efficacy. Its integration with other systems biology tools or treatment modes can enhance the cure, response rate, and control over the emergence of drug-resistant strains. Mycobacterium tuberculosis (Mtb) infection can remodel the host metabolism for its survival, while there are many biochemical pathways that the host adjusts to combat the infection. Similarly, the anti-TB vaccine, Bacillus Calmette-Guerin (BCG), was also found to affect the host metabolic pathways thus modulating immune responses. In this review, we highlight the metabolomic schema of the anti-TB vaccine and its therapeutic applications. Rewiring of immune metabolism upon BCG vaccination induces different signaling pathways which lead to epigenetic modifications underlying trained immunity. Metabolic pathways such as glycolysis, central carbon metabolism, and cholesterol synthesis play an important role in these aspects of immunity. Trained immunity and its applications are increasing day by day and it can be used to develop the next generation of vaccines to treat various other infections and orphan diseases. Our goal is to provide fresh insight into this direction and connect various dots to develop a conceptual framework.