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Characterization of Five Novel Anti-MRSA Compounds Identified Using a Whole-Animal Caenorhabditis elegans/Galleria
Rajamohammed Khader1, Nagendran Tharmalingam1, Biswajit Mishra1
1Infectious Diseases Division, Department of Medicine, Warren Alpert Medical School of Brown University, Rhode Island Hospital, Providence, RI 02903, USA.
Abstract:
There is a significant need to combat the growing challenge of antibacterial drug resistance. We have previously developed a whole-animal dual-screening platform that first used the nematode Caenorhabditis elegans, to identify low-toxicity antibacterial hits in a high-throughput format. The hits were then evaluated in the wax moth caterpillar Galleria mellonella infection model to confirm efficacy and low toxicity at a whole animal level. This multi-host approach is a powerful tool for revealing compounds that show antibacterial effects and relatively low toxicity at the whole organism level. This paper reports the use of the multi-host approach to identify and validate five new anti-staphylococcal compounds: (1) 4,4',4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol(PPT), (2) (1S,2S)-2-[2-[[3-(1H-benzimidazol-2-yl)propyl]methylamino]ethyl]-6-fluoro-1,2,3,4-tetrahydro-1-(1-methylethyl)-2-naphthalenyl cyclopropanecarboxylate dihydrochloride(NNC), (3) 4,5,6,7-tetrabromobenzotriazole (TBB), (4) 3-[2-[2-chloro-4-[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methoxy]phenyl]ethenyl] benzoic acid(GW4064), and (5) N-(cyclopropylmethoxy)-3,4,5-trifluoro-2-[(4-iodo-2-methylphenyl)amino] benzamide(PD198306). The compounds reduced the severity of methicillin-resistant Staphylococcus aureus (MRSA, strain MW2) infections in both C. elegans and G. mellonella and showed minimal inhibitory concentrations (MICs) in the range of 2-8 µg/mL. Compounds NNC, PPT, and TBB permeabilized MRSA-MW2 cells to SYTOX green, suggesting that they target bacterial membranes. Compound TBB showed synergistic activity with doxycycline and oxacillin against MRSA-MW2, and compounds PPT, NNC, GW4064, and PD198306 synergized with doxycycline, polymyxin-B, gentamicin, and erythromycin, respectively. The study demonstrates the utility of the multi-host approach with follow-up hit characterization for prioritizing anti-MRSA compounds for further evaluation.
Insights
Researchers identified five new compounds effective against drug-resistant Staphylococcus aureus using a novel whole-animal screening platform. This approach successfully validated compounds with low toxicity and significant antibacterial activity, offering new avenues for combating antimicrobial resistance.
Area of Science:
- Microbiology and Infectious Diseases
- Drug Discovery and Development
- Antimicrobial Resistance Research
Background:
- Growing challenge of antibacterial drug resistance necessitates novel therapeutic strategies.
- Previous development of a whole-animal dual-screening platform using Caenorhabditis elegans and Galleria mellonella for identifying antibacterial compounds.
- The multi-host approach effectively identifies compounds with both antibacterial efficacy and low host toxicity.
Purpose of the Study:
- To utilize the established multi-host screening platform to identify and validate new anti-staphylococcal compounds.
- To evaluate the efficacy and toxicity of identified compounds against methicillin-resistant Staphylococcus aureus (MRSA).
- To explore the mechanisms of action and synergistic potential of the validated compounds.
Main Methods:
- Application of a whole-animal dual-screening platform employing Caenorhabditis elegans and Galleria mellonella.
- Identification and validation of five anti-staphylococcal compounds: PPT, NNC, TBB, GW4064, and PD198306.
- Determination of minimal inhibitory concentrations (MICs), assessment of bacterial membrane permeabilization, and evaluation of synergistic activity with existing antibiotics.
Main Results:
- Five novel compounds (PPT, NNC, TBB, GW4064, PD198306) demonstrated reduced severity of MRSA infections in both C. elegans and G. mellonella models.
- Compounds exhibited minimal inhibitory concentrations (MICs) between 2-8 µg/mL.
- Compounds NNC, PPT, and TBB were shown to permeabilize MRSA-MW2 cells, indicating membrane targeting. Synergistic activities were observed with various antibiotics.
Conclusions:
- The multi-host screening approach is a powerful tool for prioritizing anti-MRSA compounds.
- The identified compounds represent promising candidates for further development in combating drug-resistant bacterial infections.
- Further characterization and evaluation of these compounds are warranted for potential therapeutic applications.
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