Development of new antituberculous drugs based on bacterial virulence factors interfering with host cytokine networks

Jan 19, 2011Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy

Development of new tuberculosis drugs targeting bacterial factors that disrupt the body's immune signals

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Abstract

Multidrug-resistant tuberculosis affects millions globally, necessitating urgent development of new drug targets.

The genome of Mycobacterium tuberculosis (MTB) provides insights into potential new drug targets.
MTB can evade the immune response by surviving and replicating within host macrophages.
Mycobacterial virulence factors may hinder the immune system by downregulating key protective cytokines.
Understanding the cytokine networks involved in host resistance could guide the development of innovative antituberculous drugs.
Drugs targeting bacterial virulence factors that disrupt host immune responses could enhance treatment efficacy.

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The worldwide increase in the prevalence of tuberculosis (TB), especially multidrug-resistant TB and extensively drug-resistant TB, is an important global health concern, and new effective drugs are urgently needed. Information on the genome of Mycobacterium tuberculosis (MTB) and various mycobacterial virulence genes is leading to the identification of genes that code for new drug targets. Mycobacterium tuberculosis (MTB) is resistant to the antimicrobial mechanisms of host macrophages and can survive and replicate in macrophages for long periods, resulting in a persistent infection. Mycobacterial virulence factors suppress macrophage bactericidal functions partly via their downregulatory effects on the host antimicrobial cytokine networks, consisting of proinflammatory, immunopotentiating, and Th1-inducing cytokines. Thus, for the development of unique drugs that exhibit antimycobacterial action through novel mechanisms, it is reasonable to search for targets among bacterial genes encoding virulence factors which interfere with the host cytokine responses protective to mycobacterial pathogens. In this review, we discuss the profiles of cytokine networks related to host resistance to mycobacteria, including the mechanisms of downregulation of host antimycobacterial immunity due to immunosuppressive cytokines, which are occasionally induced in the advanced stages of TB. We also highlight the development of antituberculous drugs based on bacterial virulence factors interfering with the host antimycobacterial cytokine network.

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