Attenuation of Type IV pili activity by natural products
Kerem Yalkut1, Soumaya Ben Ali Hassine1,2, Esra Basaran3
1Department of Bioengineering, Faculty of Engineering, Marmara University, Istanbul, Turkey.
Abstract:
The virulence factor Type IV pili (T4P) are surface appendages used by the opportunistic pathogen Pseudomonas aeruginosa for twitching motility and adhesion in the environment and during infection. Additionally, the use of these appendages by P. aeruginosa for biofilm formation increases its virulence and drug resistance. Therefore, attenuation of the activity of T4P would be desirable to control P. aeruginosa infections. Here, a computational approach has been pursued to screen natural products that can be used for this purpose. PilB, the elongation ATPase of the T4P machinery in P. aeruginosa, has been selected as the target subunit and virtual screening of FDA-approved drugs has been conducted. Screening identified two natural compounds, ergoloid and irinotecan, as potential candidates for inhibiting this T4P-associated ATPase in P. aeruginosa. These candidate compounds underwent further rigorous evaluation through molecular dynamics (MD) simulations and then through in vitro twitching motility and biofilm inhibition assays. Notably, ergoloid emerged as a particularly promising candidate for weakening the T4P activity by inhibiting the elongation ATPases associated with T4P. This repurposing study paves the way for the timely discovery of antivirulence drugs as an alternative to classical antibiotic treatments to help combat infections caused by P. aeruginosa and related pathogens.
Insights
Ergoloid and irinotecan show potential for inhibiting Type IV pili (T4P) in Pseudomonas aeruginosa. Ergoloid effectively weakened T4P activity, offering a new antivirulence strategy against drug-resistant infections.
Area of Science:
- Microbiology
- Drug Discovery
- Computational Biology
Background:
- Type IV pili (T4P) are crucial virulence factors for Pseudomonas aeruginosa, mediating motility, adhesion, biofilm formation, and drug resistance.
- Targeting T4P activity is a promising strategy to combat P. aeruginosa infections, offering an alternative to traditional antibiotics.
Purpose of the Study:
- To computationally screen natural products for potential inhibitors of the T4P elongation ATPase, PilB, in P. aeruginosa.
- To identify and validate drug candidates that can attenuate P. aeruginosa virulence by targeting T4P.
Main Methods:
- Virtual screening of FDA-approved natural products against the PilB ATPase.
- Molecular dynamics (MD) simulations to evaluate candidate compound interactions.
- In vitro assays to assess twitching motility and biofilm inhibition.
Main Results:
- Ergoloid and irinotecan were identified as potential inhibitors of the T4P-associated ATPase.
- Ergoloid demonstrated significant efficacy in weakening T4P activity by inhibiting elongation ATPases.
- In vitro assays confirmed the potential of ergoloid in reducing P. aeruginosa virulence.
Conclusions:
- Ergoloid is a promising candidate for repurposing as an antivirulence drug against P. aeruginosa.
- This study highlights the potential of targeting T4P machinery for developing novel therapeutic strategies.
- Drug repurposing offers a viable pathway for discovering new treatments for challenging bacterial infections.
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