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Journal of Global Antimicrobial... Jun 2021The development of drug-resistant tuberculosis (TB) is a major threat worldwide. Based on World Health Organization (WHO) reports, it is estimated that more than... (Review)
Review
The development of drug-resistant tuberculosis (TB) is a major threat worldwide. Based on World Health Organization (WHO) reports, it is estimated that more than 500 000 new cases of drug-resistant TB occur annually. In addition, there are alarming reports of increasing multidrug-resistant TB (MDR-TB) and the emergence of extensively drug-resistant TB (XDR-TB) from different countries of the world. Therefore, new options for TB therapy are required. Bedaquiline (BDQ), a novel anti-TB drug, has significant minimum inhibitory concentrations (MICs) both against drug-susceptible and drug-resistant TB. Moreover, BDQ was recently approved for therapy of MDR-TB. The current narrative review summarises the available data on BDQ resistance, describes its antimicrobial properties, and provides new perspectives on clinical use of this novel anti-TB agent.
Topics: Antitubercular Agents; Diarylquinolines; Extensively Drug-Resistant Tuberculosis; Humans; Tuberculosis, Multidrug-Resistant
PubMed: 33684606
DOI: 10.1016/j.jgar.2021.02.017 -
Journal of Microbiology (Seoul, Korea) May 2018Mycobacterium tuberculosis is the causative agent of tuberculosis (TB), a major health issue of the present era. The bacterium inhabits the host macrophage and other... (Review)
Review
Mycobacterium tuberculosis is the causative agent of tuberculosis (TB), a major health issue of the present era. The bacterium inhabits the host macrophage and other immune cells where it modulates the lysosome trafficking protein, hinders the formation of phagolysosome, and blocks the TNF receptor-dependent apoptosis of host macrophage/monocytes. Other limitations such as resistance to and low bioavailability and bio-distribution of conventional drugs aid to their high virulence and human mortality. This review highlights the use of nanotechnology-based approaches for drug formulation and delivery which could open new avenues to limit the pathogenicity of tuberculosis. Moreover phytochemicals, such as alkaloids, phenols, saponins, steroids, tannins, and terpenoids, extracted from terrestrial plants and mangroves seem promising against M. tuberculosis through different molecular mechanisms. Further understanding of the genomics and proteomics of this pathogenic microbe could also help overcome various research gaps in the path of developing a suitable therapy against tuberculosis.
Topics: Acanthaceae; Alkaloids; Antitubercular Agents; Avicennia; Genomics; Humans; Macrophages; Monocytes; Mycobacterium tuberculosis; Nanotechnology; Phenols; Phytochemicals; Plant Extracts; Plants; Proteomics; Saponins; Steroids; Tannins; Tuberculosis
PubMed: 29721825
DOI: 10.1007/s12275-018-7414-y -
Annual Review of Pathology Jan 2021(), the causative agent of tuberculosis (TB), remains a leading cause of death due to infection in humans. To more effectively combat this pandemic, many aspects of TB... (Review)
Review
(), the causative agent of tuberculosis (TB), remains a leading cause of death due to infection in humans. To more effectively combat this pandemic, many aspects of TB control must be developed, including better point of care diagnostics, shorter and safer drug regimens, and a protective vaccine. To address all these areas of need, better understanding of the pathogen, host responses, and clinical manifestations of the disease is required. Recently, the application of cutting-edge technologies to the study of pathogenesis has resulted in significant advances in basic biology, vaccine development, and antibiotic discovery. This leaves us in an exciting era of research in which our understanding of this deadly infection is improving at a faster rate than ever, and renews hope in our fight to end TB. In this review, we reflect on what is known regarding pathogenesis, highlighting recent breakthroughs that will provide leverage for the next leaps forward in the field.
Topics: Antitubercular Agents; Humans; Mycobacterium tuberculosis; Tuberculosis
PubMed: 33497258
DOI: 10.1146/annurev-pathol-042120-032916 -
Chemical Biology & Drug Design Oct 2015Tuberculosis is a contagious disease with comparatively high mortality worldwide. The statistics shows that around three million people throughout the world die annually... (Review)
Review
Tuberculosis is a contagious disease with comparatively high mortality worldwide. The statistics shows that around three million people throughout the world die annually from tuberculosis and there are around eight million new cases each year, of which developing countries showed major share. Therefore, the discovery and development of effective antituberculosis drugs with novel mechanism of action have become an insistent task for infectious diseases research programs. The literature reveals that, heterocyclic moieties have drawn attention of the chemists, pharmacologists, microbiologists, and other researchers owing to its indomitable biological potential as anti-infective agents. Among heterocyclic compounds, triazole (1,2,3-triazole/1,2,4-triazole) nucleus is one of the most important and well-known heterocycles, which is a common and integral feature of a variety of natural products and medicinal agents. Triazole core is considered as a privileged structure in medicinal chemistry and is widely used as 'parental' compounds to synthesize molecules with medical benefits, especially with infection-related activities. In the present review, we have collated published reports on this versatile core to provide an insight so that its complete therapeutic potential can be utilized for the treatment of tuberculosis. This review also explores triazole as a potential targeted core moiety against tuberculosis and various research ongoing worldwide. It is hoped that this review will be helpful for new thoughts in the quest for rational designs of more active and less toxic triazole-based antituberculosis drugs.
Topics: Animals; Antitubercular Agents; Humans; Triazoles; Tuberculosis
PubMed: 25643871
DOI: 10.1111/cbdd.12527 -
Nature Communications Jun 2023Mycobacterium tuberculosis is one of the global leading causes of death due to a single infectious agent. Pretomanid and delamanid are new antitubercular agents that...
Mycobacterium tuberculosis is one of the global leading causes of death due to a single infectious agent. Pretomanid and delamanid are new antitubercular agents that have progressed through the drug discovery pipeline. These compounds are bicyclic nitroimidazoles that act as pro-drugs, requiring activation by a mycobacterial enzyme; however, the precise mechanisms of action of the active metabolite(s) are unclear. Here, we identify a molecular target of activated pretomanid and delamanid: the DprE2 subunit of decaprenylphosphoribose-2'-epimerase, an enzyme required for the synthesis of cell wall arabinogalactan. We also provide evidence for an NAD-adduct as the active metabolite of pretomanid. Our results highlight DprE2 as a potential antimycobacterial target and provide a foundation for future exploration into the active metabolites and clinical development of pretomanid and delamanid.
Topics: Antitubercular Agents; Molecular Targeted Therapy; Mycobacterium tuberculosis; Alcohol Oxidoreductases; Nitroimidazoles; Cell Wall; Drug Resistance; Prodrugs; Spectrophotometry; NAD; Kinetics
PubMed: 37380634
DOI: 10.1038/s41467-023-39300-z -
Microbiology Spectrum Jan 2017While the immune system is credited with averting tuberculosis in billions of individuals exposed to Mycobacterium tuberculosis, the immune system is also culpable for... (Review)
Review
While the immune system is credited with averting tuberculosis in billions of individuals exposed to Mycobacterium tuberculosis, the immune system is also culpable for tempering the ability of antibiotics to deliver swift and durable cure of disease. In individuals afflicted with tuberculosis, host immunity produces diverse microenvironmental niches that support suboptimal growth, or complete growth arrest, of M. tuberculosis. The physiological state of nonreplication in bacteria is associated with phenotypic drug tolerance. Many of these host microenvironments, when modeled in vitro by carbon starvation, complete nutrient starvation, stationary phase, acidic pH, reactive nitrogen intermediates, hypoxia, biofilms, and withholding streptomycin from the streptomycin-addicted strain SS18b, render M. tuberculosis profoundly tolerant to many of the antibiotics that are given to tuberculosis patients in clinical settings. Targeting nonreplicating persisters is anticipated to reduce the duration of antibiotic treatment and rate of posttreatment relapse. Some promising drugs to treat tuberculosis, such as rifampin and bedaquiline, only kill nonreplicating M. tuberculosisin vitro at concentrations far greater than their minimal inhibitory concentrations against replicating bacilli. There is an urgent demand to identify which of the currently used antibiotics, and which of the molecules in academic and corporate screening collections, have potent bactericidal action on nonreplicating M. tuberculosis. With this goal, we review methods of high-throughput screening to target nonreplicating M. tuberculosis and methods to progress candidate molecules. A classification based on structures and putative targets of molecules that have been reported to kill nonreplicating M. tuberculosis revealed a rich diversity in pharmacophores.
Topics: Antitubercular Agents; Drug Evaluation, Preclinical; Drug Tolerance; High-Throughput Screening Assays; Microbial Viability; Mycobacterium tuberculosis
PubMed: 28233509
DOI: 10.1128/microbiolspec.TBTB2-0031-2016 -
Trends in Immunology Sep 2023Tuberculosis (TB) is the leading cause of death due to an infectious agent, with more than 1.5 million deaths attributed to TB annually worldwide. The global... (Review)
Review
Tuberculosis (TB) is the leading cause of death due to an infectious agent, with more than 1.5 million deaths attributed to TB annually worldwide. The global dissemination of drug resistance across Mycobacterium tuberculosis (Mtb) strains, causative of TB, resulted in an estimated 450 000 cases of drug-resistant (DR) TB in 2021. Dysregulated immune responses have been observed in patients with multidrug resistant (MDR) TB, but the effects of drug resistance acquisition and impact on host immunity remain obscure. In this review, we compile studies that span aspects of altered host-pathogen interactions and highlight research that explores how drug resistance and immunity might intersect. Understanding the immune processes differentially induced during DR TB would aid the development of rational therapeutics and vaccines for patients with MDR TB.
Topics: Humans; Rifampin; Antitubercular Agents; Tuberculosis; Mycobacterium tuberculosis; Tuberculosis, Multidrug-Resistant
PubMed: 37543504
DOI: 10.1016/j.it.2023.07.003 -
PLoS Pathogens Sep 2019Stewart Cole and colleagues determined the complete genome sequence of Mycobacterium tuberculosis (Mtb), the etiological agent of tuberculosis (TB), in 1998 [1]. This...
Stewart Cole and colleagues determined the complete genome sequence of Mycobacterium tuberculosis (Mtb), the etiological agent of tuberculosis (TB), in 1998 [1]. This was a landmark achievement that heralded a new age in TB drug discovery. With the genome sequence in hand, drug discoverers suddenly had thousands of new potential targets to explore. But the excitement has since faded [2]. It is unquestioned that genomics has transformed our understanding of the biology of this pathogen. However, the expectation that the Mtb genome sequence would rapidly lead to new therapeutic interventions remains unfulfilled [3]. One of the (many) reasons for this unrealized potential is that our tools to systematically interrogate the Mtb genome and its drug targets-so-called functional genomics-have been limited. In this Pearl, I argue that the recent development of robust CRISPR-based genetics in Mtb [4] overcomes many prior limitations and holds the potential to close the gap between genomics and TB drug discovery.
Topics: Antitubercular Agents; Bacterial Proteins; CRISPR-Cas Systems; Drug Delivery Systems; Drug Discovery; Genomics; Mycobacterium tuberculosis; Tuberculosis
PubMed: 31536613
DOI: 10.1371/journal.ppat.1007975 -
Thoracic Surgery Clinics Feb 2019An estimated 1.7 billion (23%) of the world's population is infected with Mycobacterium tuberculosis leading to more than 10 million new tuberculosis (TB) cases each... (Review)
Review
An estimated 1.7 billion (23%) of the world's population is infected with Mycobacterium tuberculosis leading to more than 10 million new tuberculosis (TB) cases each year. TB is one of the top 10 causes of death globally and is the leading cause of death from a single infectious disease agent. The World Health Organization's ambitious End TB Strategy aims to achieve a 95% reduction in TB deaths and 90% reduction in TB incidence rates by 2035.
Topics: Antitubercular Agents; Humans; Internationality; Mycobacterium tuberculosis; Tuberculosis; Tuberculosis, Multidrug-Resistant
PubMed: 30454918
DOI: 10.1016/j.thorsurg.2018.09.010 -
Biomedicine & Pharmacotherapy =... Feb 2024Given that the disease progression of tuberculosis (TB) is primarily related to the host's immune status, it has been gradually realized that chemotherapy that targets... (Review)
Review
Given that the disease progression of tuberculosis (TB) is primarily related to the host's immune status, it has been gradually realized that chemotherapy that targets the bacteria may never, on its own, wholly eradicate Mycobacterium tuberculosis, the causative agent of TB. The concept of host-directed therapy (HDT) with immune adjuvants has emerged. HDT could potentially interfere with infection and colonization by the pathogens, enhance the protective immune responses of hosts, suppress the overwhelming inflammatory responses, and help to attain a state of homeostasis that favors treatment efficacy. However, the HDT drugs currently being assessed in combination with anti-TB chemotherapy still face the dilemmas arising from side effects and high costs. Natural products are well suited to compensate for these shortcomings by having gentle modulatory effects on the host immune responses with less immunopathological damage at a lower cost. In this review, we first summarize the profiles of anti-TB immunology and the characteristics of HDT. Then, we focus on the rationale and challenges of developing and implementing natural products-based HDT. A succinct report of the medications currently being evaluated in clinical trials and preclinical studies is provided. This review aims to promote target-based screening and accelerate novel TB drug discovery.
Topics: Humans; Antitubercular Agents; Tuberculosis; Mycobacterium tuberculosis; Adjuvants, Immunologic; Immunity
PubMed: 38171242
DOI: 10.1016/j.biopha.2023.116087