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Scientific Reports May 2023There exists decades-old evidence that some mycobacteria, including Mycobacterium avium and Mycobacterium smegmatis, produce hydrazidase, an enzyme that can hydrolyze...
There exists decades-old evidence that some mycobacteria, including Mycobacterium avium and Mycobacterium smegmatis, produce hydrazidase, an enzyme that can hydrolyze the first-line antitubercular agent isoniazid. Despite its importance as a potential resistance factor, no studies have attempted to reveal its identity. In this study, we aimed to isolate and identify M. smegmatis hydrazidase, characterize it, and evaluate its impact on isoniazid resistance. We determined the optimal condition under which M. smegmatis produced the highest amount of hydrazidase, purified the enzyme by column chromatography, and identified it by peptide mass fingerprinting. It was revealed to be PzaA, an enzyme known as pyrazinamidase/nicotinamidase whose physiological role remains unknown. The kinetic constants suggested that this amidase with broad substrate specificity prefers amides to hydrazides as a substrate. Notably, of the five tested compounds, including amides, only isoniazid served as an efficient inducer of pzaA transcription, as revealed by quantitative reverse transcription PCR. Moreover, high expression of PzaA was confirmed to be beneficial for the survival and growth of M. smegmatis in the presence of isoniazid. Thus, our findings suggest a possible role for PzaA, and other hydrazidases yet to be identified, as an intrinsic isoniazid resistance factor of mycobacteria.
Topics: Isoniazid; Mycobacterium; Antitubercular Agents; Mycobacterium smegmatis; Amides; Mycobacterium tuberculosis
PubMed: 37210419
DOI: 10.1038/s41598-023-35213-5 -
International Journal of... 2017Worldwide, tuberculosis (TB) is still a serious and significant health concern, more so with the emergence of multidrug-resistant-TB. The inability of mankind to control... (Review)
Review
Worldwide, tuberculosis (TB) is still a serious and significant health concern, more so with the emergence of multidrug-resistant-TB. The inability of mankind to control this infection stems from the fact that the vaccines and drugs that were once effective against TB are no longer efficacious. This has led to a search for new antituberculous agents and adjuvant therapy. Vitamins are being revisited for their role in pathogenicity as well as for their antimycobacterial properties. Vitamins such as biotin and thiamin are essential for Mycobacterium tuberculosis and are required for establishment of infection. On the other hand, vitamins such as Vitamin C and Vitamin D have been shown to possess antimycobacterial properties. To combat M. tuberculosis, innovative strategies need to be devised, keeping in mind the efficacy of the agent to be used. Vitamins can prove to be useful agents capable of modifying the life cycle and biology of M. tuberculosis. We present here a brief overview of the available knowledge on thiamin, biotin, Vitamin C, and Vitamin D, keeping TB treatment and control in perspective.
Topics: Antitubercular Agents; Dietary Supplements; Humans; Mycobacterium tuberculosis; Tuberculosis; Vitamins
PubMed: 29171444
DOI: 10.4103/ijmy.ijmy_80_17 -
Journal of Microbiological Methods Feb 2021Regardless of advanced technology and innovation, infectious diseases continue to be one of the extreme health challenges in modern world. Tuberculosis (TB) is one of... (Review)
Review
Regardless of advanced technology and innovation, infectious diseases continue to be one of the extreme health challenges in modern world. Tuberculosis (TB) is one of the top ten causes of deaths worldwide and the leading cause of death from a single infectious agent. The conventional TB drug therapy requires a long term treatment with frequent and multiple drug dosing with a stiff administration schedule, which results in low patient compliance. This eventually leads to the recurrence of the infection and the emergence of multiple drug resistance. Hence, there is an urgent need to develop more successful and effective strategies to overcome the problems of drug resistance, duration of treatment course and devotion to treatment. Nanotechnology has considerable potential for diagnosis, treatment and prevention of infectious diseases including TB. The main advantages of nanoparticles to be used as drug carriers are their small size, high stability, enhanced delivery of hydrophilic and hydrophobic drugs, intracellular delivery of macromolecules, targeted delivery of drugs to specific cells or tissues, and the feasibility of various drug administration routes. Moreover, these carriers are adapted to facilitate controlled, slow, and persistent drug release from the matrix. Above properties of nanoparticles permit the improvement of drug bioavailability and reduction of dosing frequency and may reduce the toxicity and resolve the problem of low adherence to the prescribed therapy. In this review, various types of nanocarriers have been evaluated as promising drug delivery systems for different administration routes and main research outcomes in this area have been discussed.
Topics: Animals; Antitubercular Agents; Drug Carriers; Humans; Nanoparticles; Nanotechnology; Tuberculosis
PubMed: 33359155
DOI: 10.1016/j.mimet.2020.106127 -
Indian Journal of Pediatrics Jul 2024Tuberculosis (TB) has remained a global health challenge despite the availability of effective anti-tubercular drugs and various treatment strategies. Apart from the... (Review)
Review
Tuberculosis (TB) has remained a global health challenge despite the availability of effective anti-tubercular drugs and various treatment strategies. Apart from the complications related to TB disease per se, adverse effects of antitubercular therapy (ATT) also contribute to morbidity. In addition to the adverse effects, the long duration of the treatment regimen also reduces the patient's acceptability of ATT. The available "short-course treatment regimens" are still relatively long, thereby adversely affecting treatment compliance. There is a need for effective, safe, short and intensive regimens for TB which can reduce the treatment cost and adverse effects, thereby improving its acceptance. With the emergence of new evidence, the World Health Organization (WHO) has recently endorsed 4 mo short duration ATT regimen for non-severe, drug-sensitive cases of tuberculosis. Even in severe forms of disease like tubercular meningitis (TBM), trials are underway evaluating efficacy and safety of shorter regimens. Inclusion of fluroquinolones and rifapentine help shorten the regimens. These shortened regimens, however, need more close monitoring for adverse effects and may need to be converted to longer course if there is inadequate clinical response. Thus, shorter regimens for pediatric TB are likely to not only decrease the burden on patients and healthcare but also improve compliance and lower the side effects of the drugs due to prolonged exposure. This article reviews the current evidence and the guidelines pertaining to the shortened, intensive regimens for drug-sensitive tuberculosis.
Topics: Humans; Antitubercular Agents; Child; Tuberculosis; Drug Administration Schedule
PubMed: 38100071
DOI: 10.1007/s12098-023-04943-9 -
IUBMB Life Sep 2018More than a century has passed since the identification of Mycobacterium tuberculosis (Mtb) as the causative agent of tuberculosis (TB), we still are nowhere close to... (Review)
Review
More than a century has passed since the identification of Mycobacterium tuberculosis (Mtb) as the causative agent of tuberculosis (TB), we still are nowhere close to eradicating this deadly disease. Moreover, emergence of new drug-resistant strains has further complicated the situation, making it even more difficult to treat by conventional therapy regimens. Humans are the only reservoir for the existence and propagation of Mtb, which suggests that its latent forms will be most difficult to eradicate, till the human race lasts. Mtb has been associated with us for ages and its evolution is strictly guided to exploit its human host for survival and spread. The strategies employed by Mtb are unique and host specific, thereby making it hard to break this association without accurate understanding of this host-pathogen interaction. Metabolic pathways have always been at the heart of Mtb pathogenesis, with a continuous cross-talk between the pathogen and the host. Over the years, Mtb has mastered the art of manipulating the host machinery, along with modulating its own metabolism for survival in the hostile conditions. Here we aim to summarize the history of tuberculosis, its pathology and recent advances in basic understanding of the machinery, with eventual gape on the novel therapeutic strategies emerged in the past decade. © 2018 IUBMB Life, 70(9):917-925, 2018.
Topics: Animals; Antitubercular Agents; Drug Design; Host-Pathogen Interactions; Humans; Mycobacterium tuberculosis; Tuberculosis
PubMed: 30129097
DOI: 10.1002/iub.1882 -
Medicinal Research Reviews Jan 2020The causative agent of tuberculosis (TB), Mycobacterium tuberculosis and more recently totally drug-resistant strains of M. tuberculosis, display unique mechanisms to... (Review)
Review
The causative agent of tuberculosis (TB), Mycobacterium tuberculosis and more recently totally drug-resistant strains of M. tuberculosis, display unique mechanisms to survive in the host. A four-drug treatment regimen was introduced 40 years ago but the emergence of multidrug-resistance and more recently TDR necessitates the identification of new targets and drugs for the cure of M. tuberculosis infection. The current efforts in the drug development process are insufficient to completely eradicate the TB epidemic. For almost five decades the TB drug development process remained stagnant. The last 10 years have made sudden progress giving some new and highly promising drugs including bedaquiline, delamanid, and pretomanid. Many of the candidates are repurposed compounds, which were developed to treat other infections but later, exhibited anti-TB properties also. Each class of drug has a specific target and a definite mode of action. These targets are either involved in cell wall biosynthesis, protein synthesis, DNA/RNA synthesis, or metabolism. This review discusses recent progress in the discovery of newly developed and Food and Drug Administration approved drugs as well as repurposed drugs, their targets, mode of action, drug-target interactions, and their structure-activity relationship.
Topics: Animals; Antitubercular Agents; Clinical Trials as Topic; Drug Approval; Drug Evaluation, Preclinical; Humans; Molecular Targeted Therapy; Structure-Activity Relationship
PubMed: 31254295
DOI: 10.1002/med.21602 -
Nature Reviews. Drug Discovery Jun 2024Antimicrobial resistance poses a significant threat to the sustainability of effective treatments against the three most prevalent infectious diseases: malaria, human... (Review)
Review
Antimicrobial resistance poses a significant threat to the sustainability of effective treatments against the three most prevalent infectious diseases: malaria, human immunodeficiency virus (HIV) infection and tuberculosis. Therefore, there is an urgent need to develop novel drugs and treatment protocols capable of reducing the emergence of resistance and combating it when it does occur. In this Review, we present an overview of the status and underlying molecular mechanisms of drug resistance in these three diseases. We also discuss current strategies to address resistance during the research and development of next-generation therapies. These strategies vary depending on the infectious agent and the array of resistance mechanisms involved. Furthermore, we explore the potential for cross-fertilization of knowledge and technology among these diseases to create innovative approaches for minimizing drug resistance and advancing the discovery and development of new anti-infective treatments. In conclusion, we advocate for the implementation of well-defined strategies to effectively mitigate and manage resistance in all interventions against infectious diseases.
Topics: Humans; Malaria; HIV Infections; Tuberculosis; Antitubercular Agents; Animals; Antimalarials
PubMed: 38750260
DOI: 10.1038/s41573-024-00933-4 -
BMJ (Clinical Research Ed.) Mar 2020Guidelines on the treatment of tuberculosis (TB) have essentially remained the same for the past 35 years, but are now starting to change. Ongoing clinical trials will...
Guidelines on the treatment of tuberculosis (TB) have essentially remained the same for the past 35 years, but are now starting to change. Ongoing clinical trials will hopefully transform the landscape for treatment of drug sensitive TB, drug resistant TB, and latent TB infection. Multiple trials are evaluating novel agents, repurposed agents, adjunctive host directed therapies, and novel treatment strategies that will increase the probability of success of future clinical trials. Guidelines for HIV-TB co-infection treatment continue to be updated and drug resistance testing has been revolutionized in recent years with the shift from phenotypic to genotypic testing and the concomitant increased speed of results. These coming changes are long overdue and are sorely needed to address the vast disparities in global TB incidence rates. TB is currently the leading cause of death globally from a single infectious agent, but the work of many researchers and the contributions of many patients in clinical trials will reduce the substantial global morbidity and mortality of the disease.
Topics: Antitubercular Agents; Humans; Latent Tuberculosis; Practice Guidelines as Topic; Tuberculosis; Tuberculosis, Multidrug-Resistant
PubMed: 32122882
DOI: 10.1136/bmj.m216 -
Methods in Molecular Biology (Clifton,... 2020Mycobacterium tuberculosis (Mtb) is a bacterial pathogen that causes a potentially serious infectious disease called tuberculosis (TB). Cyclohexapeptide wollamides A and...
Mycobacterium tuberculosis (Mtb) is a bacterial pathogen that causes a potentially serious infectious disease called tuberculosis (TB). Cyclohexapeptide wollamides A and B were recently isolated from Streptomyces nov. sp. (MST-115088) and subsequently reported to show excellent in vitro antituberculosis activity with minimum inhibitory concentration (MIC) of 1.56 μg/mL against Mtb (H37Rv) and favorable selectivity profile. This chapter describes the detailed synthesis of antitubercular wollamide analogs using solid-phase synthesis of linear hexapeptide precursors, followed by solution-phase HBTU-mediated macrocyclization and global side chain deprotection.
Topics: Antitubercular Agents; Cyclization; Magnetic Resonance Spectroscopy; Microbial Sensitivity Tests; Molecular Structure; Mycobacterium tuberculosis; Peptides, Cyclic; Solid-Phase Synthesis Techniques
PubMed: 31879925
DOI: 10.1007/978-1-0716-0227-0_11 -
Frontiers in Cellular and Infection... 2020Tuberculosis (TB) was responsible for more deaths in 2019 than any other infectious agent. This epidemic is exacerbated by the ongoing development of multi-drug... (Review)
Review
Tuberculosis (TB) was responsible for more deaths in 2019 than any other infectious agent. This epidemic is exacerbated by the ongoing development of multi-drug resistance and HIV co-infection. Recent studies have therefore focused on identifying host-directed therapies (HDTs) that can be used in combination with anti-mycobacterial drugs to shorten the duration of TB treatment and improve TB outcomes. In searching for effective HDTs for TB, studies have looked toward immunometabolism, the study of the role of metabolism in host immunity and, in particular, the Warburg effect. Across a variety of experimental paradigms ranging from systems to the clinic, studies on the role of the Warburg effect in TB have produced seemingly conflicting results and contradictory conclusions. To reconcile this literature, we take a historical approach to revisit the definition of the Warburg effect, re-examine the foundational papers on the Warburg effect in the cancer field and explore its application to immunometabolism. With a firm context established, we assess the literature investigating metabolism and immunometabolism in TB for sufficient evidence to support the role of the Warburg effect in TB immunity. The effects of the differences between animal models, species of origin of the macrophages, duration of infection and strains used for these studies are highlighted. In addition, the shortcomings of using 2-deoxyglucose as an inhibitor of glycolysis are discussed. We conclude by proposing experimental criteria that are essential for future studies on the Warburg effect in TB to assist with the research for HDTs to combat TB.
Topics: Animals; Antitubercular Agents; Glycolysis; Macrophages; Mycobacterium tuberculosis; Tuberculosis
PubMed: 33072629
DOI: 10.3389/fcimb.2020.576596