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Nat Microbiol. 2019 Jun;4(6):972-984. doi: 10.1038/s41564-019-0395-8. Epub 2019 Mar 25.

Targeting Type IV pili as an antivirulence strategy against invasive meningococcal disease.

Denis K1,2,3, Le Bris M1,2,3, Le Guennec L1,2,3, Barnier JP4,5,6,7, Faure C1,2,3, Gouge A1,2,3, Bouzinba-Ségard H1,2,3, Jamet A4,5,6,7, Euphrasie D4,5,6,7, Durel B1,2,3, Barois N8,9,10,11, Pelissier P12, Morand PC1,2,3, Coureuil M4,5,6, Lafont F8,9,10,11, Join-Lambert O4,5,6,7, Nassif X4,5,6,7, Bourdoulous S13,14,15.

Author information

1
U1016, Institut Cochin, Inserm, Paris, France.
2
UMR8104, CNRS, Paris, France.
3
Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
4
U1151, Institut Necker Enfants Malades, Inserm, Paris, France.
5
UMR 8253, CNRS, Paris, France.
6
Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
7
Hôpital Necker Enfants Malades, Assistance Publique - Hôpitaux de Paris, Paris, France.
8
Cellular Microbiology and Physics of Infection Group, Centre for Infection and Immunity of Lille, Institut Pasteur de Lille, Lille, France.
9
UMR 8204, CNRS, Lille, France.
10
U1019, Inserm, Lille, France.
11
Université de Lille, Lille, France.
12
Service de Chirurgie Reconstructrice et Plastique, Fondation Hôpital Saint Joseph, Paris, France.
13
U1016, Institut Cochin, Inserm, Paris, France. sandrine.bourdoulous@inserm.fr.
14
UMR8104, CNRS, Paris, France. sandrine.bourdoulous@inserm.fr.
15
Université Paris Descartes, Sorbonne Paris Cité, Paris, France. sandrine.bourdoulous@inserm.fr.

Abstract

Bacterial virulence factors are attractive targets for the development of therapeutics. Type IV pili, which are associated with a remarkable array of properties including motility, the interaction between bacteria and attachment to biotic and abiotic surfaces, represent particularly appealing virulence factor targets. Type IV pili are present in numerous bacterial species and are critical for their pathogenesis. In this study, we report that trifluoperazine and related phenothiazines block functions associated with Type IV pili in different bacterial pathogens, by affecting piliation within minutes. Using Neisseria meningitidis as a paradigm of Gram-negative bacterial pathogens that require Type IV pili for pathogenesis, we show that piliation is sensitive to altered activity of the Na+ pumping NADH-ubiquinone oxidoreductase (Na+-NQR) complex and that these compounds probably altered the establishment of the sodium gradient. In vivo, these compounds exert a strong protective effect. They reduce meningococcal colonization of the human vessels and prevent subsequent vascular dysfunctions, intravascular coagulation and overwhelming inflammation, the hallmarks of invasive meningococcal infections. Finally, they reduce lethality. This work provides a proof of concept that compounds with activity against bacterial Type IV pili could beneficially participate in the treatment of infections caused by Type IV pilus-expressing bacteria.

PMID:
30911127
DOI:
10.1038/s41564-019-0395-8
[Indexed for MEDLINE]

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