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Archives of Pharmacal Research Jun 2017Mycobacterium tuberculosis is responsible for severe mortality and morbidity worldwide but, under-developed and developing countries are more prone to infection. In... (Review)
Review
Mycobacterium tuberculosis is responsible for severe mortality and morbidity worldwide but, under-developed and developing countries are more prone to infection. In search of effective and wide-spectrum anti-tubercular agents, interdisciplinary approaches are being explored. Of the several approaches used, computer based quantitative structure activity relationship (QSAR) have gained momentum. Structure-based drug design and discovery implies a combined knowledge of accurate prediction of ligand poses with the good prediction and interpretation of statistically validated models derived from the 3D-QSAR approach. The validated models are generally used to screen a small combinatorial library of potential synthetic candidates to identify hits which further subjected to docking to filter out compounds as novel potential emerging drug molecules to address multidrug-resistant tuberculosis. Several newer models are integrated to QSAR methods which include different types of chemical and biological data, and simultaneous prediction of pharmacological activities including toxicities and/or other safety profiles to get new compounds with desired activity. In the process, several newer molecules have been identified which are now being assessed for their clinical efficacy. Present review deals with the advances made in the field highlighting overall future prospects of the development of anti-tuberculosis drugs.
Topics: Animals; Antitubercular Agents; Drug Design; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Quantitative Structure-Activity Relationship; Tuberculosis
PubMed: 28456911
DOI: 10.1007/s12272-017-0914-1 -
The Indian Journal of Tuberculosis Jan 2022Tuberculosis (TB) continues to be a major cause of death worldwide that can be effectively treated with timely diagnosis and treatment. With the advent of nuclear... (Review)
Review
Tuberculosis (TB) continues to be a major cause of death worldwide that can be effectively treated with timely diagnosis and treatment. With the advent of nuclear imaging techniques like Fluorine Fluoro-2-Deoxy-D-Glucose Positron Emission Tomography (F-FDG) PET/CT, the diagnosis of tuberculosis, particularly its extrapulmonary forms, has received great impetus in cases where microbiological confirmation cannot be achieved. Although detection of mycobacteria either by staining, culture or nucleic acid amplification techniques still form the gold standard of diagnosis, newer diagnostic techniques are always welcome in the field which can expedite clinical management. Use of radiolabeled antibiotics is one such evolving sphere which needs further research. Moving ahead from radiolabeled leukocytes, antibiotics are being increasingly focused upon to act as a vehicle to locate infectious lesions. Antibiotics like ciprofloxacin have been labeled with diagnostic radionuclides such as Technetium-99m (Tc-99m) and used to image many infectious diseases with encouraging results in TB. However, the nonspecific attributes of ciprofloxacin have hindered its growth to assist the diagnosis of TB. A novel approach would be to utilize ethambutol, a specific antitubercular agent, which has been found to be safe and effective in the diagnosis of TB in the available published studies. Ethambutol is known to be taken up specifically by tubercular lesions. This forms the basis of using Tc-99m labelled ethambutol for imaging TB lesions. An added advantage would be its ability to differentiate tubercular from malignant and fungal lung lesions that are the usual differentials in patients suspected of having TB. Most of the studies involving ethambutol have been done in skeletal TB and its validation in other forms of TB is still awaited. Recently the role of PET-CT has also been explored in human studies using C Rifampicin to study the antibiotic uptake in tubercular lesions. This review summarizes the available evidence regarding diagnosis of TB by radiolabeled antibiotic imaging to emphasize the need for accelerated research in the fight against TB.
Topics: Antitubercular Agents; Fluorodeoxyglucose F18; Humans; Positron Emission Tomography Computed Tomography; Radionuclide Imaging; Tuberculosis
PubMed: 35074146
DOI: 10.1016/j.ijtb.2021.03.012 -
The New England Journal of Medicine Mar 2023
Topics: Humans; Tuberculosis; Antitubercular Agents; Time Factors
PubMed: 36807402
DOI: 10.1056/NEJMe2300413 -
Current Drug Metabolism 2015Treatment regimen recommended for resistant tuberculosis consists of various drugs and these drugs are prescribed for at least 12-15 months. Such a long duration therapy... (Review)
Review
Treatment regimen recommended for resistant tuberculosis consists of various drugs and these drugs are prescribed for at least 12-15 months. Such a long duration therapy and high dose of antibiotics result in adverse drug reactions (ADRs). ADRs may lead to various complications in disease management like replacement of drugs, dose increment, therapy withdrawal, etc. Linezolid is one of those drugs, practiced as an anti-mycobacterial agent and it is an important member of drug regimen for MDR and XDR tuberculosis. Linezolid is a broad spectrum antibiotic known for its unique mechanism of inhibition of resistant pathogenic strains. However, it causes serious adverse effects like thrombocytopenia, optic neuropathy, peripheral neuropathy, lactic acidosis, etc. Literature suggests that Linezolid can cause severe ADRs which affect patient compliance and hinder in therapy to a larger extent. Recent studies confirm the possibility of ADRs to be predicted with genetic make-up of individuals. To effectively deliver the available treatment regimen and ensure patient compliance, it is important to manage ADRs more efficiently. The role of pharmacogenomics in reducing adverse drug effects has been recently explored. In the present review, we discussed about Linezolid induced adverse drug reactions, mechanisms and genetic associations.
Topics: Animals; Anti-Bacterial Agents; Antitubercular Agents; Drug-Related Side Effects and Adverse Reactions; Humans; Linezolid; Thrombocytopenia
PubMed: 26424176
DOI: 10.2174/1389200216666151001121004 -
Trends in Microbiology Mar 2024The aetiologic agent of tuberculosis (TB), Mycobacterium tuberculosis (Mtb), can survive, persist, and proliferate in a variety of heterogeneous subcellular... (Review)
Review
The aetiologic agent of tuberculosis (TB), Mycobacterium tuberculosis (Mtb), can survive, persist, and proliferate in a variety of heterogeneous subcellular compartments. Therefore, TB chemotherapy requires antibiotics crossing multiple biological membranes to reach distinct subcellular compartments and target these bacterial populations. These compartments are also dynamic, and our understanding of intracellular pharmacokinetics (PK) often represents a challenge for antitubercular drug development. In recent years, the development of high-resolution imaging approaches in the context of host-pathogen interactions has revealed the intracellular distribution of antibiotics at a new level, yielding discoveries with important clinical implications. In this review, we describe the current knowledge regarding cellular PK of antibiotics and the complexity of drug distribution within the context of TB. We also discuss the recent advances in quantitative imaging and highlight their applications for drug development in the context of how intracellular environments and microbial localisation affect TB treatment efficacy.
Topics: Humans; Tuberculosis; Antitubercular Agents; Mycobacterium tuberculosis; Host-Pathogen Interactions; Treatment Outcome
PubMed: 37709598
DOI: 10.1016/j.tim.2023.08.009 -
Mini Reviews in Medicinal Chemistry 2022Tuberculosis (TB) is an acute or chronic infectious disease caused by several species of Mycobacterium, collectively called tubercle bacilli or Mycobacterium... (Review)
Review
BACKGROUND
Tuberculosis (TB) is an acute or chronic infectious disease caused by several species of Mycobacterium, collectively called tubercle bacilli or Mycobacterium tuberculosis complex. Around 10 million people get sick with tuberculosis (TB) each year. TB is the second leading cause of death today after HIV/AIDS. A serious problem in the context of MDR-TB is the extensively drug-resistant TB, which is an important reason for the restricted chemotherapy in TB. Therefore, there is a need to explore new antitubercular (anti-TB) agents. Coumarin is an oxygencontaining heterocyclic compound and can be widely found in many natural products, and many of them display diverse biological activities. The wide spectrum of activities of coumarin molecules has intrigued the scientists to explore the natural coumarins and their synthetic derivatives for their potential as anti-TB drugs.
OBJECTIVE
The objective of this review is to emphasize important coumarin analogs with anti-TB activities and their structure-activity relationships (SAR) for designing better anti-TB agents.
METHOD
Latest, authentic and published reports on various synthetic and natural coumarin derivatives and their anti-TB activities is being thoroughly studied and analyzed. The structural requirements of coumarins as anti-TB drugs have also been studied.
RESULT
Collection and compilation of reports on various synthetic and natural coumarin derivatives and their anti-TB activities are being performed.
CONCLUSION
The study provides the latest report on coumarin derivatives synthesized as anti-TB agent and whether their activity depends on structural changes or not.
Topics: Antitubercular Agents; Coumarins; Drug Design; Extensively Drug-Resistant Tuberculosis; Humans; Mycobacterium tuberculosis
PubMed: 34579635
DOI: 10.2174/1389557521666210927124511 -
Cell Mar 2023The emergence of drug-resistant tuberculosis has created an urgent need for new anti-tubercular agents. Here, we report the discovery of a series of macrolides called...
The emergence of drug-resistant tuberculosis has created an urgent need for new anti-tubercular agents. Here, we report the discovery of a series of macrolides called sequanamycins with outstanding in vitro and in vivo activity against Mycobacterium tuberculosis (Mtb). Sequanamycins are bacterial ribosome inhibitors that interact with the ribosome in a similar manner to classic macrolides like erythromycin and clarithromycin, but with binding characteristics that allow them to overcome the inherent macrolide resistance of Mtb. Structures of the ribosome with bound inhibitors were used to optimize sequanamycin to produce the advanced lead compound SEQ-9. SEQ-9 was efficacious in mouse models of acute and chronic TB as a single agent, and it demonstrated bactericidal activity in a murine TB infection model in combination with other TB drugs. These results support further investigation of this series as TB clinical candidates, with the potential for use in new regimens against drug-susceptible and drug-resistant TB.
Topics: Animals; Mice; Antitubercular Agents; Macrolides; Drug Resistance, Bacterial; Mycobacterium tuberculosis; Clarithromycin
PubMed: 36827973
DOI: 10.1016/j.cell.2023.01.043 -
Revue de Pneumologie Clinique 2015The emergence of drug-resistant TB in many countries has become a major public health problem and an obstacle to effective tuberculosis control. Multidrug-resistant... (Review)
Review
The emergence of drug-resistant TB in many countries has become a major public health problem and an obstacle to effective tuberculosis control. Multidrug-resistant tuberculosis (MDR-TB), which is most often the result of poor adherence, is a particularly dangerous form of tuberculosis because it is caused by bacilli resistant to at least isoniazid and rifampicin, the two most effective anti-tuberculosis drugs. Techniques for rapid diagnosis of resistance have greatly improved the care of patients by allowing early treatment which remains complex and costly establishment, and requires skills and resources. The treatment is not standardized but it includes in all cases attack phase with five drugs (there must be an injectable agent and a fluoroquinolone that form the basis of the regimen) for eight months and a maintenance phase (without injectable agent) with a total duration of 20 months on average. Surgery may be beneficial as long as the lesions are localized and the patient has a good cardiorespiratory function. Evolution of MDR-TB treated is less favorable than tuberculosis with germ sensitive. The cure rate varies from 60 to 75% for MDR-TB, and drops to 30 to 40% for XDR-TB. Mortality remains high, ranging from 20 to 40% even up to 70-90% in people co-infected with HIV.
Topics: Antitubercular Agents; Extensively Drug-Resistant Tuberculosis; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Practice Guidelines as Topic; Risk Factors; Treatment Outcome; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; World Health Organization
PubMed: 25153927
DOI: 10.1016/j.pneumo.2014.05.001 -
Bioorganic & Medicinal Chemistry Letters Jan 2023The emergence of drug resistant Mycobacterium tuberculosis, the causative agent of tuberculosis, demands the development of new drugs and new drug targets. We have...
The emergence of drug resistant Mycobacterium tuberculosis, the causative agent of tuberculosis, demands the development of new drugs and new drug targets. We have recently reported that the d-phenylalanine benzoxazole Q112 has potent antibacterial activity against this pathogen with a distinct mechanism of action from other antimycobacterial agents. Q112 and previously reported derivatives were unstable in plasma and no free compound could be observed. Here we expand the structure-activity relationship for antimycobacterial activity and find nonhydrolyzable derivatives with decreased plasma binding. We also show that there is no correlation between antibacterial activity and inhibition of PanG, a putative target for these compounds.
Topics: Humans; Mycobacterium tuberculosis; Benzoxazoles; Antitubercular Agents; Tuberculosis, Multidrug-Resistant; Tuberculosis; Structure-Activity Relationship; Microbial Sensitivity Tests
PubMed: 36572353
DOI: 10.1016/j.bmcl.2022.129116 -
The International Journal of... Nov 2016Carbapenems, a more recent β-lactam class, represent a unique anti-tuberculosis option, as emerging evidence demonstrates that they target the Mycobacterium... (Review)
Review
Carbapenems, a more recent β-lactam class, represent a unique anti-tuberculosis option, as emerging evidence demonstrates that they target the Mycobacterium tuberculosis cell wall and β-lactamase. This provides a potentially new agent against M. tuberculosis, in particular for multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB), where options are limited. In this review, we examine the current evidence on the activity of carbapenems against M. tuberculosis. The predominance of work is in vitro, and suggests that carbapenems kill M. tuberculosis at least in the active phase, with possible greater potency with the addition of a β-lactamase inhibitor. The few in vivo and clinical studies suggest that there are benefits and that they are generally tolerated, although the variability in duration, dosing, and background regimen and lack of pharmacokinetic analyses limit interpretation of efficacy. We outline further areas of research to better understand the role of carbapenems to add a needed new agent to the treatment of MDR- and XDR-TB.
Topics: Animals; Antitubercular Agents; Carbapenems; Cell Wall; Disease Models, Animal; Drug Resistance, Multiple, Bacterial; Extensively Drug-Resistant Tuberculosis; Humans; Incidence; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Prevalence; Randomized Controlled Trials as Topic; beta-Lactamases
PubMed: 27776583
DOI: 10.5588/ijtld.16.0498