Inhibiting Type VI Secretion System Activity with a Biomimetic Peptide Designed To Target the Baseplate Wedge Complex

Y. Cherrak (1) , I. Filella-Merce (2, 3) , V. Schmidt (1) , D. Byrne (4) , V. Sgoluppi (1) , R. Chaiaheloudjou (1) , S. Betzi (5) , X. Morelli (5) , M. Nilges (2) , R. Pellarin (2) , E. Durand (6)

1 LISM - Laboratoire d'ingénierie des systèmes macromoléculaires
2 Bioinformatique structurale - Structural Bioinformatics
3 ED 515 - Complexité du vivant
4 IMM - Institut de Microbiologie de la Méditerranée
5 CRCM - Centre de Recherche en Cancérologie de Marseille
6 LISM - Laboratoire d'Ingéniérie et Science des Matériaux - EA 4695

Human health is threatened by bacterial infections that are increasingly resistant to multiple drugs. A recently emerged strategy consists of disarming pathogenic bacteria by targeting and blocking their virulence factors. The type VI secretion system (T6SS) is a widespread secretion nanomachine encoded and employed by pathogenic strains to establish their virulence process during host invasion. Given the conservation of T6SS in several human bacterial pathogens, the discovery of an effective broad-spectrum T6SS virulence blocker represents an attractive target for development of antivirulence therapies. Here, we identified and validated a protein-protein interaction interface, TssK-TssG, as a key factor in the assembly of the T6SS baseplate (BP) complex in the pathogen enteroaggregative Escherichia coli (EAEC). In silico and biochemical studies revealed that the determinants of the interface are broadly conserved among pathogenic species, suggesting a role for this interface as a target for T6SS inhibition. Based on the high-resolution structure of the TssKFGE wedge complex, we rationally designed a biomimetic cyclic peptide (BCP) that blocks the assembly of the EAEC BP complex and inhibits the function of T6SS in bacterial cultures. Our BCP is the first compound completely designed from prior structural knowledge with anti-T6SS activity that can be used as a model to target human pathogens.

Mots clés: bacterial secretion system; type VI secretion system; T6SS; bioinformatic; biomimetic peptide; protein-protein interface; virulence inhibitor

Domaines: Sciences du Vivant [q-bio]

Y. Cherrak, I. Filella-Merce, V. Schmidt, D. Byrne, V. Sgoluppi, et al.. Inhibiting Type VI Secretion System Activity with a Biomimetic Peptide Designed To Target the Baseplate Wedge Complex. mBio, 2021, 12 (4), ⟨10.1128/mbio.01348-21⟩. ⟨pasteur-03429012⟩