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Trends in Microbiology Jun 2018In this infographic, the genetics, phylogeny, physiology, and pathogenesis mechanisms of Mycobacterium tuberculosis are shown. Mycobacterium tuberculosis is the...
In this infographic, the genetics, phylogeny, physiology, and pathogenesis mechanisms of Mycobacterium tuberculosis are shown. Mycobacterium tuberculosis is the etiological agent of tuberculosis (TB), the leading cause of death due to a single infectious agent, claiming 1.7 million lives in 2016. Of the deaths attributable to TB in 2016, 22% occurred in people coinfected with HIV, and close to 5% of the 10.4 million incident cases of this disease were resistant to at least two of the first-line TB drugs. In this infographic, we describe the fundamental features of the genetics, phylogeny, and physiology of this member of the phylum Actinobacteria, which is associated increasingly with drug resistance mediated by mutations and rearrangements in its single, circular chromosome. We also highlight the key pathogenesis mechanisms employed by this slow-growing, facultative intracellular bacterium, which include avoidance of host cell clearance by arrest of the normal macrophage maturation process.
Topics: Antitubercular Agents; Drug Resistance, Bacterial; Humans; Macrophages; Mycobacterium tuberculosis; Phylogeny; Tuberculosis
PubMed: 29580884
DOI: 10.1016/j.tim.2018.02.012 -
International Journal of Molecular... Mar 2023(), the causative agent of TB, is a recalcitrant pathogen that is rife around the world, latently infecting approximately a quarter of the worldwide population. The... (Review)
Review
(), the causative agent of TB, is a recalcitrant pathogen that is rife around the world, latently infecting approximately a quarter of the worldwide population. The asymptomatic status of the dormant bacteria escalates to the transmissible, active form when the host's immune system becomes debilitated. The current front-line treatment regimen for drug-sensitive (DS) strains is a 6-month protocol involving four different drugs that requires stringent adherence to avoid relapse and resistance. Poverty, difficulty to access proper treatment, and lack of patient compliance contributed to the emergence of more sinister drug-resistant (DR) strains, which demand a longer duration of treatment with more toxic and more expensive drugs compared to the first-line regimen. Only three new drugs, bedaquiline (BDQ) and the two nitroimidazole derivatives delamanid (DLM) and pretomanid (PMD) were approved in the last decade for treatment of TB-the first anti-TB drugs with novel mode of actions to be introduced to the market in more than 50 years-reflecting the attrition rates in the development and approval of new anti-TB drugs. Herein, we will discuss the pathogenesis, current treatment protocols and challenges to the TB control efforts. This review also aims to highlight several small molecules that have recently been identified as promising preclinical and clinical anti-TB drug candidates that inhibit new protein targets in .
Topics: Humans; Antitubercular Agents; Tuberculosis; Mycobacterium tuberculosis; Drug Delivery Systems; Clinical Protocols; Tuberculosis, Multidrug-Resistant
PubMed: 36982277
DOI: 10.3390/ijms24065202 -
Clinical and Experimental Allergy :... Mar 2022Tuberculosis (TB) is the commonest cause of death by a single infectious agent globally and ranks amongst the top ten causes of global mortality. The incidence of TB is... (Review)
Review
Tuberculosis (TB) is the commonest cause of death by a single infectious agent globally and ranks amongst the top ten causes of global mortality. The incidence of TB is highest in Low-Middle Income countries (LMICs). Prompt institution of, and compliance with, therapy are cornerstones for a favourable outcome in TB and to mitigate the risk of multiple drug resistant (MDR)-TB, which is challenging to treat. There is some evidence that adverse drug reactions (ADRs) and hypersensitivity reactions (HSRs) to anti-TB drugs occur in over 60% and 3%-4% of patients respectively. Both ADRs and HSRs represent significant barriers to treatment adherence and are recognised risk factors for MDR-TB. HSRs to anti-TB drugs are usually cutaneous and benign, occur within few weeks after commencement of therapy and are likely to be T-cell mediated. Severe and systemic T-cell mediated HSRs and IgE mediated anaphylaxis to anti-TB drugs are relatively rare, but important to recognise and treat promptly. T-cell-mediated HSRs are more frequent amongst patients with co-existing HIV infection. Some patients develop multiple sensitisation to anti-TB drugs. Whilst skin tests, patch tests and in vitro diagnostics have been used in the investigation of HSRs to anti-TB drugs, their predictive value is not established, they are onerous, require specialist input of an allergist and are resource-dependent. This is compounded by the global, unmet demand for allergy specialists, particularly in low-income countries (LICs)/LMICs and now the challenging circumstances of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. This narrative review provides a critical analysis of the limited published evidence on this topic and proposes a cautious and pragmatic approach to optimise and standardise the management of HSRs to anti-TB drugs. This includes clinical risk stratification and a dual strategy involving sequential re-challenge and rapid drug desensitisation. Furthermore, a concerted international effort is needed to generate real-time data on ADRs, HSRs, safety and clinical outcomes of these interventions.
Topics: Anaphylaxis; Antitubercular Agents; COVID-19; Drug Hypersensitivity; Humans; SARS-CoV-2
PubMed: 34939251
DOI: 10.1111/cea.14084 -
The European Respiratory Journal Jun 2021Antimicrobial resistance is a major public health problem globally. Likewise, forms of tuberculosis (TB) resistant to first- and second-line TB medicines present a major... (Review)
Review
Antimicrobial resistance is a major public health problem globally. Likewise, forms of tuberculosis (TB) resistant to first- and second-line TB medicines present a major challenge for patients, healthcare workers and healthcare services. In November 2019, the World Health Organization (WHO) convened an independent international expert panel to review new evidence on the treatment of multidrug- (MDR) and rifampicin-resistant (RR) TB, using the Grading of Recommendations Assessment, Development and Evaluation approach.Updated WHO guidelines emerging from this review, published in June 2020, recommend a shorter treatment regimen for patients with MDR/RR-TB not resistant to fluoroquinolones (of 9-11 months), with the inclusion of bedaquiline instead of an injectable agent, making the regimen all oral. For patients with MDR-TB and additional fluoroquinolone resistance, a regimen composed of bedaquiline, pretomanid and linezolid may be used under operational research conditions (6-9 months). Depending on the drug-resistance profile, extent of TB disease or disease severity, a longer (18-20 months) all-oral, individualised treatment regimen may be used. In addition, the review of new data in 2019 allowed the WHO to conclude that there are no major safety concerns on the use of bedaquiline for >6 months' duration, the use of delamanid and bedaquiline together and the use of bedaquiline during pregnancy, although formal recommendations were not made on these topics.The 2020 revision has highlighted the ongoing need for high-quality evidence and has reiterated the need for clinical trials and other research studies to contribute to the development of evidence-based policy.
Topics: Antitubercular Agents; Drug Therapy, Combination; Female; Humans; Linezolid; Pregnancy; Tuberculosis, Multidrug-Resistant; World Health Organization
PubMed: 33243847
DOI: 10.1183/13993003.03300-2020 -
Mini Reviews in Medicinal Chemistry 2018Tuberculosis (TB) is a primordial infectious disease that mainly affects the lungs. M. tuberculosis (Mycobacterium tuberculosis) is the etiological agent of TB and... (Review)
Review
Tuberculosis (TB) is a primordial infectious disease that mainly affects the lungs. M. tuberculosis (Mycobacterium tuberculosis) is the etiological agent of TB and currently more than one-third of the world population is suffering from TB. For the treatment of TB, administration of multiple antibiotics such as isoniazid, rifampicin, pyrazinamide and ethambutol is required for a long period of time to kill bacteria. However, antibiotic resistance is an emerging problem in multiple drug-resistant tuberculosis (MDR-TB) infections. World Health Organization (WHO) has developed a novel strategy called DOTS (directly observed treatment, short-course), in which specific combination of anti-TB drugs is given to control TB. In this review article we have focused on the comprehensive management of TB and have provided the valuable information about first and second line anti-TB drugs, DOTS and novel drug delivery systems to be used against M. tuberculosis. Important aspects related to new anti-TB drugs and vaccines in various stages of clinical development are also covered in this article.
Topics: Animals; Antitubercular Agents; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Tuberculosis, Pulmonary
PubMed: 27553018
DOI: 10.2174/1389557516666160823160010 -
Nature Reviews. Immunology Nov 2017Infection with Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), results in a range of clinical presentations in humans. Most infections manifest as... (Review)
Review
Infection with Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), results in a range of clinical presentations in humans. Most infections manifest as a clinically asymptomatic, contained state that is termed latent TB infection (LTBI); a smaller subset of infected individuals present with symptomatic, active TB. Within these two seemingly binary states, there is a spectrum of host outcomes that have varying symptoms, microbiologies, immune responses and pathologies. Recently, it has become apparent that there is diversity of infection even within a single individual. A good understanding of the heterogeneity that is intrinsic to TB - at both the population level and the individual level - is crucial to inform the development of intervention strategies that account for and target the unique, complex and independent nature of the local host-pathogen interactions that occur in this infection. In this Review, we draw on model systems and human data to discuss multiple facets of TB biology and their relationship to the overall heterogeneity observed in the human disease.
Topics: Animals; Antitubercular Agents; Disease Models, Animal; Disease Susceptibility; Granuloma; Host-Pathogen Interactions; Humans; Mycobacterium tuberculosis; Patient Outcome Assessment; Treatment Outcome; Tuberculosis
PubMed: 28736436
DOI: 10.1038/nri.2017.69 -
Clinics in Chest Medicine Dec 2019Mycobacterium tuberculosis is a major public health concern and requires prompt treatment. Goals of treatment include curing the individual patient and protecting the... (Review)
Review
Mycobacterium tuberculosis is a major public health concern and requires prompt treatment. Goals of treatment include curing the individual patient and protecting the community from ongoing tuberculosis transmission. To achieve durable cure, regimens must include multiple agents given concurrently and in a manner to ensure completion of therapy. This article focuses on preferred regimens of drug-susceptible tuberculosis under current guidelines by the American Thoracic Society, Centers for Disease Control and Prevention, and Infectious Diseases Society of America and World Health Organization. In addition, topics including patient centered care, poor treatment outcomes, and adverse effects are also discussed.
Topics: Antitubercular Agents; Humans; Treatment Outcome; Tuberculosis
PubMed: 31731983
DOI: 10.1016/j.ccm.2019.07.006 -
International Journal of Antimicrobial... Sep 2022Tuberculosis (TB) remains one of the leading causes of death by a communicable agent, infecting up to one-quarter of the world's population, predominantly in... (Review)
Review
Tuberculosis (TB) remains one of the leading causes of death by a communicable agent, infecting up to one-quarter of the world's population, predominantly in disadvantaged communities. Pharmacometrics employ quantitative mathematical models to describe the relationships between pharmacokinetics and pharmacodynamics, and to predict drug doses, exposures and responses. Pharmacometric approaches have provided a scientific basis for improved dosing of anti-TB drugs and concomitantly administered antiretrovirals at the population level. The development of modelling frameworks including physiologically based pharmacokinetics, quantitative systems pharmacology and machine learning provides an opportunity to extend the role of pharmacometrics to in-silico quantification of drug-drug interactions, prediction of doses for special populations, dose optimization and individualization, and understanding the complex exposure-response relationships of multi-drug regimens in terms of both efficacy and safety, informing regimen design for future study. This short, clinically focused review explores what has been done, and what opportunities exist for pharmacometrics to impact TB pharmacotherapy.
Topics: Antitubercular Agents; Drug Interactions; Humans; Models, Theoretical; Tuberculosis
PubMed: 35724859
DOI: 10.1016/j.ijantimicag.2022.106620 -
Current Medicinal Chemistry 2018Due to the importance of nature as a source of new drug candidates, the purpose of this article is to emphasize the marine natural products, which exhibit antitubercular... (Review)
Review
Due to the importance of nature as a source of new drug candidates, the purpose of this article is to emphasize the marine natural products, which exhibit antitubercular activity, published between January 2000 and May 2016, with 138 quotations to 250 compounds obtained from marine resources. These metabolites are organized by chemical constitution and named as simple alkyl lipids derivatives, aromatics derivatives, peptides, alkaloids, terpenoids, steroids, macrolides, and polycyclic polyketides.
Topics: Antitubercular Agents; Biological Products; Microbial Sensitivity Tests; Molecular Structure; Mycobacterium tuberculosis
PubMed: 28088903
DOI: 10.2174/0929867324666170113120221 -
International Journal of Molecular... Jun 2023(Mtb) is the etiological agent of tuberculosis (TB), a disease that, although preventable and curable, remains a global epidemic due to the emergence of resistance and... (Review)
Review
(Mtb) is the etiological agent of tuberculosis (TB), a disease that, although preventable and curable, remains a global epidemic due to the emergence of resistance and a latent form responsible for a long period of treatment. Drug discovery in TB is a challenging task due to the heterogeneity of the disease, the emergence of resistance, and uncomplete knowledge of the pathophysiology of the disease. The limited permeability of the cell wall and the presence of multiple efflux pumps remain a major barrier to achieve effective intracellular drug accumulation. While the complete genome sequence of Mtb has been determined and several potential protein targets have been validated, the lack of adequate models for in vitro and in vivo studies is a limiting factor in TB drug discovery programs. In current therapeutic regimens, less than 0.5% of bacterial proteins are targeted during the biosynthesis of the cell wall and the energetic metabolism of two of the most important processes exploited for TB chemotherapeutics. This review provides an overview on the current challenges in TB drug discovery and emerging Mtb druggable proteins, and explains how chemical probes for protein profiling enabled the identification of new targets and biomarkers, paving the way to disruptive therapeutic regimens and diagnostic tools.
Topics: Humans; Antitubercular Agents; Mycobacterium tuberculosis; Tuberculosis; Bacterial Proteins; Drug Discovery
PubMed: 37445660
DOI: 10.3390/ijms241310482