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Drug Repositioning as a Therapeutic Strategy against Streptococcus pneumoniae: Cell Membrane as Potential Target
Laura Ortiz-Miravalles1,2,3, Manuel Sánchez-Angulo4, Jesús M Sanz1,5
1Protein Engineering against Antimicrobial Resistance Group, Centro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas (CSIC), 28040 Madrid, Spain.
Repurposing existing drugs offers new antimicrobial strategies against Streptococcus pneumoniae. Seven compounds from the Prestwick Chemical Library demonstrated significant growth inhibition and membrane disruption, paving the way for novel antibacterial drug design.
Area of Science:
- Microbiology
- Pharmacology
- Drug Discovery
Background:
- Streptococcus pneumoniae is a major respiratory pathogen.
- Novel antimicrobial strategies are urgently needed due to rising resistance.
- Drug repurposing offers a faster route to new therapeutics.
Purpose of the Study:
- To screen a library of repurposed drugs for antimicrobial activity against Streptococcus pneumoniae.
- To identify specific compounds that inhibit pneumococcal growth and viability.
- To explore the mechanism of action, particularly effects on bacterial membrane permeability.
Main Methods:
- Screening of the Prestwick Chemical Library (1200 compounds) against planktonic Streptococcus pneumoniae cultures.
- Multi-round selection process to identify effective compounds.
- Determination of minimal inhibitory concentrations (MICs) and bacterial viability.
- Assessment of bacterial membrane permeability changes.
Main Results:
- Seven compounds, including clofilium tosylate and amiodarone hydrochloride, were identified.
- These compounds inhibited pneumococcal growth and reduced bacterial viability by 90.0%-99.9% at 25 µM.
- Most compounds increased bacterial membrane permeability, suggesting a membrane-targeting mechanism.
- A common chemical structure (aliphatic amine linked to phenyl moiety) was identified.
Conclusions:
- Drug repurposing is a viable strategy for discovering new antimicrobials against Streptococcus pneumoniae.
- The identified compounds show potential as novel antibacterial agents.
- The shared chemical structure provides a basis for designing new membrane-active antimicrobials.
