No abstract

The rapid increase in pathogenic microorganisms with antimicrobial resistant profiles has become a significant public health problem globally. The management of this issue using conventional antimicrobial preparations frequently results in an increase in pathogen resistance and a shortage of effective antimicrobials for future use against the same pathogens. In this review, we discuss the emergence of AMR and argue for the importance of addressing this issue by discovering novel synthetic or naturally occurring antibacterial compounds and providing insights into the application of various drug delivery approaches, delivered through numerous routes, in comparison with conventional delivery systems. In addition, we discuss the effectiveness of these delivery systems in different types of infectious diseases associated with antimicrobial resistance. Finally, future considerations in the development of highly effective antimicrobial delivery systems to combat antimicrobial resistance are presented.

Drug discovery is a complex process, and the use of a comprehensive approach is deemed necessary to discover new chemical entities with novel mechanisms of action. This research was carried out to determine whether Drosophila melanogaster can serve as an appropriate model organism in the initial screening of drug candidates with immunomodulatory activities. To test this, we performed phenotypic assay and molecular analysis to investigate the immunomodulatory activities of aspirin, dexamethasone, curcumin, and epigallocatechin gallate (EGCG), that have been reported to yield such effects in the mammalian model system. In vivo survival analysis demonstrated that all drugs/compounds were relatively safe at the tested concentrations. In the infection assay, curcumin and EGCG showed a protective signature to bacterial infection in flies lacking Toll-mediated immune responses. Furthermore, dexamethasone and aspirin, drugs with immunosuppressive activity, could improve the survival of PGRP-LBΔ mutant flies with hyperactivated immune system. These phenotypes were supported by RT-qPCR-based molecular analysis, revealing that drugs/compounds used in this study could modulate the expression level of genes related to the immune system. In conclusion, while curcumin and EGCG could promote the improvement of fly survival against infection, aspirin and dexamethasone were able to suppress overactivation of immune responses in D. melanogaster. These results are in line with the ones observed in the mammalian model system, further emphasizing the notion that flies would serve as a prospective model organism in the initial screening of drug candidates for their immunomodulatory activities prior to further checking in the mammalian animal models. In the end, this will reduce the use of mammalian animal models for preliminary experiments in an effort to discover/repurpose drugs with immunomodulatory activity.

The activation of the NF-kB pathway leading to the production of proinflammatory cytokines is a critical feature in innate antiviral immunity. However, in SARS-CoV-2 infection, a high number of cases with a prolonged late-stage stimulation of cytokine production that leads to a cytokine storm phenotype, an undesirable, dangerous immune-related state that can cause multiple organ failures, have been reported. To treat this, immunosuppressants with selective action on the innate NF-kB pathway are urgently required. Bitter gourd (Momordica charantia L.) has been reported to yield anti-inflammatory activity, thus might be a potential candidate for such effort. In this study, we carried out experimental procedures on the PGRP-LB mutant line of Drosophila melanogaster to examine the immunosuppressive effect of Momordica charantia L. fruit extract (MCFE) on the NF-kB pathway. Initial phytochemical screening revealed that Momordica charantia L. fruit extract contains alkaloids, flavonoids, tannins, and saponins. Furthermore, the phenotypical analysis demonstrated that MCFE could improve the survival and locomotor of the PGRP-LB mutant line of Drosophila melanogaster in a concentration-dependent manner. Additional gene expression analysis revealed that the expression of dpt and dro, two important downstream genes in the Imd (NF-kB) pathway of D. melanogaster, was significantly reduced, in a different expression profile, in response to MCFE treatment. However, it is important to note that while the expression of dpt was dramatically repressed in all extract-treated groups, the expression of dro occurred in a concentration-dependent manner. These results strongly support the notion that Momordica charantia L. can reduce the expression of proinflammatory cytokines downstream of the NF-kB pathway, hence potential to be used as a source candidate to harvest prospective immunosuppressive compounds to alleviate the cytokine storm condition.