Mycobacterium tuberculosis, the etiological agent of tuberculosis (TB), is an extremely successful pathogen that adapts to survive within the host. During the latency phase of infection, M. tuberculosis employs a range of effector proteins to be cloud the host immune system and shapes its lifestyle to reside in granulomas, sophisticated, and organized structures of immune cells that are established by the host in response to persistent infection. While normally being restrained in immunocompetent hosts, M. tuberculosis within granulomas can cause the recrudescence of TB when host immunity is compromised. Aside from causing TB, accumulating evidence suggests that M. tuberculosis is also associated with multiple other human diseases, such as pulmonary complications, autoimmune diseases, and metabolic syndromes. Furthermore, it has been recently appreciated that M. tuberculosis infection can also reciprocally interact with the human microbiome, which has a strong link to immune balance and health. In this review, we highlight the adaptive survival of M. tuberculosis within the host and provide an overview for regulatory mechanisms underlying interactions between M. tuberculosis infection and multiple important human diseases. A better understanding of how M. tuberculosis regulates the host immune system to cause TB and reciprocally regulates other human diseases is critical for developing rational treatments to better control TB and help alleviate its associated comorbidities.

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Mycobacterium tuberculosis: An Adaptable Pathogen Associated With Multiple Human Diseases

It is essential to acknowledge the efforts made thus far to manage or eliminate various disease burden faced by humankind. However, the rising global trends of the so-called incurable diseases continue to put pressure on Pharma industries and other drug discovery platforms. In the past, drugs with more than one target were deemed as undesirable options with interest being on the one-drug-single target. Despite the successes of the single-target drugs, it is currently beyond doubt that these drugs have limited efficacy against complex diseases in which the pathogenesis is dependent on a set of biochemical events and several bioreceptors operating concomitantly. Different approaches have thus been proposed to come up with effective drugs to combat even the complex diseases. In the past, the focus was on producing drugs from screening plant compounds; today, we talk about combination therapy and multi-targeting drugs. The multi-target drugs have recently attracted much attention as promising tools to fight against most challenging diseases, and thus a new research focus area. This review will discuss the potential impact of multi-target drug approach on various complex diseases with focus on malaria, tuberculosis (TB), diabetes and neurodegenerative diseases as the main representatives of multifactorial diseases. We will also discuss alternative ideas to solve the current problems bearing in mind the fourth industrial revolution on drug discovery.

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Potential Impact of the Multi-Target Drug Approach in the Treatment of Some Complex Diseases

Human tuberculosis (TB) is amongst the oldest and deadliest human bacterial diseases that pose major health, social and economic burden at a global level Current regimens for TB treatment are lengthy, expensive and ineffective to emerging drug resistant strains Thus, there is an urgent need for identification and development of novel TB drugs and drug regimens with comprehensive and specific mechanisms of action Many medicinal plants are traditionally used for TB treatment While some of their phytochemical composition has been elucidated, their mechanisms of action are not well understood Insufficient knowledge on Mycobacterium tuberculosis (Mtb) biology and the complex nature of its infection limit the effectiveness of current screening-based methods used for TB drug discovery Nonetheless, application of metabolomics tools within the ‘omics’ approaches, could provide an alternative method of elucidating the mechanism of action of medicinal plants Metabolomics aims at high throughput detection, quantification and identification of metabolites in biological samples Changes in the concentration of specific metabolites in a biological sample indicate changes in the metabolic pathways In this paper review and discuss novel methods that involve application of metabolomics to drug discovery and the understanding of mechanisms of action of medicinal plants with anti-TB activity Current knowledge on TB infection, anti-TB drugs and mechanisms of action are also included We further highlight metabolism of M tuberculosis and the potential drug targets, as well as current approaches in the development of anti-TB drugs

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Application of metabolomics to drug discovery and understanding the mechanisms of action of medicinal plants with anti-tuberculosis activity

Anti-mycobacterial activity of some medicinal plants used traditionally by tribes from Madhya Pradesh, India for treating tuberculosis related symptoms.

Artemisia afra, a controversial herbal remedy or a treasure trove of new drugs?

CONTEXT Traditionally used plants for treating chest-related problems/tuberculosis (TB) have not been evaluated in detail and hence a thorough study is needed in this regard. This knowledge may find application in developing new anti-TB drugs. OBJECTIVE This article elaborates on studying the activity of medicinal plants against different forms of Mycobacterium tuberculosis (Mtb) using different model strains, in vitro and ex vivo assays for studying the tuberculocidal activity and discusses the results from different studies on the activity against different forms of Mtb and human immunodeficiency virus-tuberculosis (HIV-TB) co-infection. METHODS Scientific databases such as PubMed, Elsevier, Scopus, Google scholar, were used to retrieve the information from 86 research articles (published from 1994 to 2016) related to the topic of this review. RESULTS Twenty-three plant species have been reported to possess active molecules against multi-drug resistant (MDR) isolates of Mtb. Seven plants were found to be active against intracellular Mtb and six against dormant bacilli. Seven plants were synergistically effective when combined with anti-TB drugs. Six studies suggest that the beneficial effects of plant extracts are due to their wide array of immuno-modulatory effects manifested by the higher expression of cytokines. Some studies have also shown the dual activity (anti-HIV and anti-TB) of plants. CONCLUSION We emphasize on identifying plants based on traditional uses and testing their extracts/phytomolecules against MDR strains, intracellular Mtb as well as against dormant Mtb. This will help in future to shorten the current therapeutic regimens for TB and also for treating HIV-TB co-infection.

Anupam Kaushik

Papers

Anti-mycobacterial activity of some medicinal plants used traditionally by tribes from Madhya Pradesh, India for treating tuberculosis related symptoms.

Plants in our combating strategies against Mycobacterium tuberculosis: progress made and obstacles met.