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    New antivirulence strategy against life-threatening meningococcal invasive disease identified

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    A study diriged by Sandrine Bourdoulous

    Despite prompt antibiotics treatment, infectious diseases caused by invasive bacterial pathogens, such as Neisseria meningitidis (meningococcus), responsible for meningitis and rapidly progressive and severe sepsis, remain often fatal or leading to permanent organ damage, cognitive impairment, and physical disability. The team of Dr Sandrine Bourdoulous, directrice de recherche CNRS at the Institut Cochin (CNRS/Inserm/Université Paris Descartes) has identified a family of compounds that target a major virulence factor, found in most pathogenic bacteria. These molecules represents promising adjuvant therapy for the treatment of invasive meningococcal disease and other bacterial diseases.

    Many investigations have been made in recent years to improve the treatment of infectious diseases in the face of incomplete or adverse effects of antibiotics, as well as increasing antibiotic resistance. Among new targets for antibacterial compounds, type IV pili appear as particularly promising. These are long filamentous structures present in numerous bacterial species and associated with a remarkable array of bacterial properties ranging from motility to adhesion to host cells, which are critical for their pathogenesis.

    Among bacteria requiring type IV pili for pathogenesis, Neisseria meningitidis (also known as meningococcus) is one of the most harmful. Meningococci normally reside asymptomatically on the human nasopharyngeal mucosa. However, they are pathogenic when they gain access to the bloodstream, as they can provoke two rare but devastating diseases, purpura fulminans and meningitis, rapidly causing death or permanent disability despite prompt antibiotics treatments. Type IV pili are required for circulating meningococci to adhere to and colonize the endothelium lining blood vessels in several organs including skin, liver, brain, and kidney, a process rapidly leading to vascular injury, disseminated intravascular coagulation and acute inflammation, contributing to hemorrhagic skin necrosis and multiple organ failure.

    The team of Dr Sandrine Bourdoulous has identified a family of compounds, which rapidly promote the loss of type IV pili and, subsequently, alter all the functions carried by these structures, including adherence to human endothelial cells.

    In collaboration with the team of Pr Xavier Nassif, Institut Necker Enfants Malades (CNRS/Inserm/Université Paris Descartes/AP-HP), they show in a humanized mouse model that these compounds exert a strong protective effect against the deleterious events occurring during meningococcemia. They reduce colonization of the human vessels by circulating meningococci and prevent subsequent vascular dysfunctions, intravascular coagulation and overwhelming inflammation, the hallmarks of invasive meningococcal infections. Finally, they reduce lethality. In association with antibiotics, they reduce signs of skin lesions. This work provides proof of concept that targeting Type IV pili is an efficient antivirulence strategy against invasive meningococcal disease.

     The identified molecules belongs to phenothiazines, a family of compounds previously used in human medicine to treat psychotic disorders. Among those, thioridazine was very well tolerated and effective at dose regimen compatible with human use. It is therapeutically safe with few side effects when used with moderation, as proven by the 60 plus years it has been in use. Although it is difficult to predict from mice study how effective thioridazine might be on the outcome of an infection in human, the data obtained strongly suggest that it could prevent the deleterious consequences of invasive meningococcal diseases. More generally, due to the well-conserved set of proteins involved in type IV pilus biosynthesis in Gram-negative bacteria, including pathogenic bacteria such as P. aeruginosa, interfering with type IV pilus-mediated host cell interaction represents an attractive strategy to modify the course of diseases induced by these pathogens.

     Taken together, through an unexpected regulation of bacterial type IV pili expression by phenothiazines, this work reveals a new approach to reduce meningococcal vascular colonization and subsequent vascular lesions and lethality, as well as the benefit of such molecules as adjuvant therapy for the treatment of invasive meningococcal disease. This provides proof of concept that compounds with an activity against bacterial type IV pili could be used in addition to antibiotics to prevent and treat bacterial diseases.

    The reported compounds have been patented for this new purpose.

     

    Figure legend:

    massive thrombosis of human dermal vessel infected by Neisseria meningitidis. Staining: vessel (collagen IV, red), bacteria (green), thrombus (platelets, pink), nuclei (blue).

     

    Reference

    Targeting Type IV pili as an antivirulence strategy against invasive meningococcal disease.
    Denis K, Le Bris M, Le Guennec L, Barnier JP, Faure C, Gouge A, Bouzinba-Ségard H, Jamet A, Euphrasie D, Durel B, Barois N, Pelissier P, Morand PC, Coureuil Lafont F, M, Join-Lambert O, Nassif Xand Bourdoulous S.  Nature Microbiol,

     

    Patents

    Use of phenothiazine derivative in the treatment of infectious purpura or purpura fulminans. WO/2018/083314. Bourdoulous S, Denis K, Le Guennec L.

    Use of phenothiazine derivative in the treatment of infections caused by bacteria carrying type IV pili. WO/2019/008141. Bourdoulous S, Denis K, Le Guennec L.

     

    Researcher contact

    Sandrine Bourdoulous () - +33(0)1 40 51 64 27