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A Screening Method for Identification of Heterochromatin-Promoting Drugs Using Drosophila
Published on: March 12, 2020
An iron-chelating sulfonamide identified from Drosophila-based screening for antipathogenic discovery
Yeon-Ji Yoo1, In-Young Chung1, Shivakumar S Jalde2
1Department of Pharmacy, College of Pharmacy and Institute of Pharmaceutical Sciences, CHA University, Seongnam, Korea.
Abstract:
We exploited bacterial infection assays using the fruit fly Drosophila melanogaster to identify anti-infective compounds that abrogate the pathological consequences in the infected hosts. Here, we demonstrated that a pyridine-3-N-sulfonylpiperidine derivative (4a) protects Drosophila from the acute infections caused by bacterial pathogens including Pseudomonas aeruginosa. 4a did not inhibit the growth of P. aeruginosa in vitro, but inhibited the production of secreted toxins such as pyocyanin and hydrogen cyanide, while enhancing the production of pyoverdine and pyochelin, indicative of iron deprivation. Based on its catechol moiety, 4a displayed iron-chelating activity in vitro toward both iron (II) and iron (III), more efficiently than the approved iron-chelating drugs such as deferoxamine and deferiprone, concomitant with more potent antibacterial efficacy in Drosophila infections and unique transcriptome profile. Taken together, these results delineate a Drosophila-based strategy to screen for antipathogenic compounds, which interfere with iron uptake crucial for bacterial virulence and survival in host tissues.
Insights
A novel compound protects fruit flies from bacterial infections by chelating iron, hindering pathogen virulence. This discovery offers a new strategy for developing anti-infective drugs targeting bacterial iron uptake.
Area of Science:
- Microbiology
- Pharmacology
- Genetics
Background:
- Bacterial infections pose significant health threats, necessitating novel therapeutic strategies.
- The fruit fly *Drosophila melanogaster* serves as a valuable model organism for studying host-pathogen interactions and screening anti-infective compounds.
Purpose of the Study:
- To identify anti-infective compounds using *Drosophila melanogaster* infection models.
- To investigate the mechanism of action of a pyridine-3-N-sulfonylpiperidine derivative (4a) against bacterial pathogens.
Main Methods:
- Bacterial infection assays were performed in *Drosophila melanogaster* using *Pseudomonas aeruginosa*.
- In vitro assays were conducted to assess compound 4a's effect on bacterial growth, toxin production, and iron-chelating activity.
- Transcriptome profiling was employed to analyze the host's response to compound 4a treatment.
Main Results:
- Compound 4a demonstrated protective efficacy against *P. aeruginosa* infections in *Drosophila*.
- 4a inhibited bacterial toxin production (pyocyanin, hydrogen cyanide) and enhanced siderophore production (pyoverdine, pyochelin), indicating iron deprivation.
- 4a exhibited potent in vitro iron-chelating activity, surpassing established drugs like deferoxamine and deferiprone.
Conclusions:
- Compound 4a represents a promising anti-infective agent targeting bacterial iron acquisition.
- The *Drosophila* model is effective for discovering antipathogenic compounds that disrupt essential bacterial processes.
- Interfering with iron uptake is a viable strategy for combating bacterial virulence and host tissue survival.
