Antimicrobial Resistance (AMR) is a critical global health challenge, and in this review article, we examine the limitations of traditional therapeutic methods and the emerging role of alternative therapies. By examining the reasons behind the failure of conventional treatments, including the inadequacy of one-drug-one-enzyme approaches, the complex evolution of AMR, and the impact of drug biotransformation, we better understand why conventional treatments failed. Moreover, the review discusses several alternative therapies, including RNA-based treatments, aptamers, peptide-based therapies, phage therapy, and probiotics, discussing their applications, advantages, and limitations. Additionally, we discuss the obstacles to develop these therapies, including funding shortages, regulatory barriers, and public perception. This comprehensive analysis aims to provide insight into the future of AMR, emphasizing the need for innovative strategies and practical approaches.

Rifampicin (RIF) is one of the most valued drugs in the treatment of tuberculosis. TB treatment relies on a combination therapy and for multidrug-resistant strains may include β-lactams.

The field of immunotherapy has undergone radical conceptual changes over the last decade. There are various examples of immunotherapy, including the use of monoclonal antibodies, cancer vaccines, tumor-infecting viruses, cytokines, adjuvants, and autologous T cells carrying chimeric antigen receptors (CARs) that can bind cancer-specific antigens known as adoptive immunotherapy. While a lot has been achieved in the field of T-cell immunotherapy, only a fraction of patients (20%) see lasting benefits from this mode of treatment, which is why there is a critical need to turn our attention to other immune cells. B cells have been shown to play both anti- and pro-tumorigenic roles in tumor tissue. In this review, we shed light on the dual nature of B cells in the tumor microenvironment. Furthermore, we discussed the different factors affecting the biology and function of B cells in tumors. In the third section, we described B-cell-based immunotherapies and their clinical applications and challenges. These current studies provide a springboard for carrying out future mechanistic studies to help us unleash the full potential of B cells in immunotherapy.

M. tuberculosis N-acetyl-glucosamine-1-phosphate uridyltransferase (GlmU_Mtb) is a bi-functional enzyme engaged in the synthesis of two metabolic intermediates N-acetylglucosamine-1-phosphate (GlcNAc-1-P) and UDP-GlcNAc, catalyzed by the C- and N-terminal domains respectively. UDP-GlcNAc is a key metabolite essential for the synthesis of peptidoglycan, disaccharide linker, arabinogalactan and mycothiols. While glmU_Mtb was predicted to be an essential gene, till date the role of GlmU_Mtb in modulating the in vitro growth of Mtb or its role in survival of pathogen ex vivo / in vivo have not been deciphered. Here we present the results of a comprehensive study dissecting the role of GlmU_Mtb in arbitrating the survival of the pathogen both in vitro and in vivo. We find that absence of GlmU_Mtb leads to extensive perturbation of bacterial morphology and substantial reduction in cell wall thickness under normoxic as well as hypoxic conditions. Complementation studies show that the acetyl- and uridyl- transferase activities of GlmU_Mtb are independently essential for bacterial survival in vitro, and GlmU_Mtb is also found to be essential for mycobacterial survival in THP-1 cells as well as in guinea pigs. Depletion of GlmU_Mtb from infected murine lungs, four weeks post infection, led to significant reduction in the bacillary load. The administration of Oxa33, a novel oxazolidine derivative that specifically inhibits GlmU_Mtb, to infected mice resulted in significant decrease in the bacillary load. Thus our study establishes GlmU_Mtb as a strong candidate for intervention measures against established tuberculosis infections. The synthesis of the Mtb cell wall involves a cascade of reactions catalyzed by cytosolic and cell membrane-bound enzymes. The reaction catalyzed by GlmU_Mtb (an enzyme with acetyltransferase and uridyltransferase activities) generates UDP-GlcNAc, a central nucleotide-sugar building block of the cell wall. Apart from cell wall synthesis UDP-GlcNAc is an essential metabolite participating in other cellular processes including disaccharide linker and mycothiol biosynthesis. GlmU_Mtb shares very little sequence similarity with eukaryotic acetyltransferase and uridyltransferase enzymes. Many pathogens have alternative pathway(s) for foraging GlcNAc from the host. The present study was undertaken to see the effects of depleting GlmU_Mtb on pathogen survival in the host animal. We have generated a conditional gene replacement mutant of glmU_Mtb and find that depletion of GlmU_Mtb at any stage of bacterial growth or in mice infected with Mtb including a well-established infection, results in irreversible bacterial death due to perturbation of cell wall synthesis. We have developed a novel anti-GlmU_Mtb inhibitor (Oxa33), identified its binding site on GlmU_Mtb, and shown its specificity for GlmU_Mtb. The study demonstrates that GlmU_Mtb is a promising target for therapeutic intervention and Oxa33 can be pursued as a lead molecule.