Polypharmacology Approaches against the Pseudomonas aeruginosa MvfR Regulon and Their Application in Blocking Virulence and Antibiotic Tolerance

Damien Maura; Steffen L. Drees; Arunava Bandyopadhaya; Tomoe Kitao; Michele Negri; Melissa Starkey; Biliana Lesic; Sylvain Milot; Eric Déziel; Robert Zahler; Mike Pucci; Antonio Felici; Susanne Fetzner; François Lépine; Laurence G. Rahme

Polypharmacology Approaches against the Pseudomonas aeruginosa MvfR Regulon and Their Application in Blocking Virulence and Antibiotic Tolerance

Damien Maura ^{1, 2, 3} Steffen L. Drees ⁴ Arunava Bandyopadhaya ^{1, 2, 3} Tomoe Kitao ^{1, 2, 3} Michele Negri ⁵ Melissa Starkey ^{1, 2, 3} Biliana Lesic ² Sylvain Milot ⁶ Eric Déziel ⁶ Robert Zahler ⁷ Mike Pucci ⁷ Antonio Felici ⁵ Susanne Fetzner ⁴ François Lépine ⁶ Laurence G. Rahme ^{1, 2, 3, *}

* Corresponding author

1 HMS - Harvard Medical School [Boston]

2 Shriners Hospitals for Children [Boston]

3 Massachusetts General Hospital [Boston]

4 WWU - Westfälische Wilhelms-Universität Münster

5 Aptuit

6 INRS-IAF - Institut Armand Frappier

7 Spero Therapeutics

Abstract : Pseudomonas aeruginosa is an important nosocomial pathogen that is frequently recalcitrant to available antibiotics, underlining the urgent need for alternative therapeutic options against this pathogen. Targeting virulence functions is a promising alternative strategy as it is expected to generate less-selective resistance to treatment compared to antibiotics. Capitalizing on our nonligand-based benzamide-benzimidazole (BB) core structure compounds reported to efficiently block the activity of the P. aeruginosa multiple virulence factor regulator MvfR, here we report the first class of inhibitors shown to interfere with PqsBC enzyme activity, responsible for the synthesis of the MvfR activating ligands HHQ and PQS, and the first to target simultaneously MvfR and PqsBC activity. The use of these compounds reveals that inhibiting PqsBC is sufficient to block P. aeruginosa's acute virulence functions, as the synthesis of MvfR ligands is inhibited. Our results show that MvfR remains the best target of this QS pathway, as we show that antagonists of this target block both acute and persistence-related functions. The structural properties of the compounds reported in this study provide several insights that are instrumental for the design of improved MvfR regulon inhibitors against both acute and persistent P. aeruginosa infections. Moreover, the data presented offer the possibility of a polypharmacology approach of simultaneous silencing two targets in the same pathway. Such a combined antivirulence strategy holds promise in increasing therapeutic efficacy and providing alternatives in the event of a single target's resistance development.

Document type :

Journal articles

Domain :

Life Sciences [q-bio]

Life Sciences [q-bio] / Pharmaceutical sciences / Pharmacology

Complete list of metadatas

https://hal-riip.archives-ouvertes.fr/pasteur-01534493
Contributor : Michel Courcelles <>
Submitted on : Wednesday, June 7, 2017 - 4:25:24 PM
Last modification on : Tuesday, August 6, 2019 - 1:30:03 PM

Polypharmacology Approaches against the Pseudomonas aeruginosa MvfR Regulon and Their Application in Blocking Virulence and Antibiotic Tolerance

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Polypharmacology Approaches against the Pseudomonas aeruginosa MvfR Regulon and Their Application in Blocking Virulence and Antibiotic Tolerance

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