Abstract

The past few decades have seen alarming rates of antimicrobial drug resistance. This trend paralleled a lack of conventional methods of discovery of antibiotics with novel mechanisms of action. Although use of mammalian models remains indispensable for preclinical testing of new antimicrobial compounds, combating emerging multidrug-resistant microbial pathogens may require the use of robust, high-throughput experimental systems that can accelerate drug development. The recent discovery of striking similarities in innate immune signaling pathways between Drosophila melanogaster and mammals has led to a surge in the use of this minihost as an alternative model in studying a variety of infectious diseases. Several genetic screens for microbial pathogenicity in Drosophila identified virulence traits shown to be important for infection in mammals that may serve as targets for future drug development. In addition, conventional antimicrobial agents retain full activity in D. melanogaster infection models, which may pave the way for use of this minihost for high-throughput antimicrobial drug screening. Finally, the availability of genetic tools that allow for conditional inactivation of almost every gene in D. melanogaster is anticipated to result in the discovery of novel immunomodulatory mechanisms of action of newly identified antimicrobial compounds. Overall, the powerful genetics of and capacity for large-scale screening in D. melanogaster make this minihost a promising complementary model that may result in a new paradigm in antimicrobial drug discovery. However, antimicrobial drug discovery in such heterologous, phylogenetically disparate minihosts as the fruit flies, would still require further validation in mammalian models.

Keywords: Drosophila melanogaster, antimicrobials, mini-host models, drug discovery, high-throughput screening, melanogaster, indispensable, immunocompromised, pathogenicity, phylogenetically, transcriptomes, peptidoglycan, metchnikowin, drosomycin, diptericin, attacin, cecropin, inoculum, Aspergillus, siderophore