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ethambutol AND mechanism of action

Rafal Sawicki, Joanna Golus, Agata Przekora, Agnieszka Ludwiczuk, Elwira Sieniawska, Grazyna Ginalska
The purpose of the study was to evaluate the antimycobacterial activity and the possible action mode of cinnamon bark essential oil and its main constituent-cinnamaldehyde-against the Mycobacterium tuberculosis ATCC 25177 strain. Cinnamaldehyde was proved to be the main bioactive compound responsible for mycobacterial growth inhibition and bactericidal effects. The antimycobacterial activity of cinnamaldehyde was found to be comparable with that of ethambutol, one of the first-line anti-TB antibiotics. The selectivity index determined using cell culture studies in vitro showed a high biological potential of cinnamaldehyde...
September 18, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Rafael Baptista, David M Fazakerley, Manfred Beckmann, Les Baillie, Luis A J Mur
Pretomanid is a promising anti-tubercular drug currently at clinical phase III, but its mechanisms of action are currently unclear. This study aimed to: (i) reveal the metabolome of Mycobacterium smegmatis under pretomanid treatment; (ii) compare major sources of metabolite variation in bacteria treated with pretomanid treatment and other antibiotics; and (iii) to target metabolites responsible for the killing activity of pretomanid in mycobacteria. Untargeted high-resolution metabolite profiling was carried out using flow infusion electrospray ion high resolution mass spectrometry (FIE-HRMS) to identify and quantify metabolites...
March 23, 2018: Scientific Reports
Jordana Galizia, Mariano Prado Acosta, Estefanía Urdániz, Marcelo A Martí, Mariana Piuri
Nitroxyl (HNO) is a highly elusive and reactive molecule. Nitroxyl biological effects and pharmacological potential are becoming increasingly relevant. Mycobacterium tuberculosis infection needs new and more efficient drugs. Reactive Nitrogen and Oxygen Species (RNOS) are key compounds used by the immune system to fight intracellular infections, particularly Mycobacterium tuberculosis. In this context, we analyzed HNO potential to kill mycobacteria. We evaluated the viability and biological response of mycobacteria towards HNO releasing compounds...
March 2018: Tuberculosis
Luciana Dias Ghiraldi-Lopes, Paula Aline Zanetti Campanerut-Sa, Geisa Paulino Caprini Evaristo, Jean Eduardo Meneguello, Adriana Fiorini, Vanessa Pietrowski Baldin, Emanuel Maltempi de Souza, Regiane Bertin de Lima Scodro, Vera Lucia Dias Siqueira, Rosilene Fressatti Cardoso
BACKGROUND: In recent years, very few effective drugs against Mycobacterium tuberculosis (M. tb) have emerged which motivates the research with drugs already used in the treatment of tuberculosis. EMB is a bacteriostatic drug that affects cell wall integrity, but the effects of this drug on bacilli are not fully exploited. OBJECTIVE: Based on the need to better investigate the complex mechanism of action of EMB, our study presented the proteome profile of M. tb after different times of EMB exposure, aiming to comprehend the dynamics of bacilli response to its effects...
January 24, 2018: Infectious Disorders Drug Targets
Elwira Sieniawska, Rafal Sawicki, Marta Swatko-Ossor, Agnieszka Napiorkowska, Agata Przekora, Grazyna Ginalska, Ewa Augustynowicz-Kopec
Background : On account of emergence of multi- and extensively drug-resistant Mycobacterium tuberculosis (Mtb) strains, combinations of drugs with natural compounds were tested to search for antibiotic activity enhancers. In this work we studied terpenes (α-pinene, bisabolol, β-elemene, ( R )-limonene, ( S )-limonene, myrcene, sabinene), which are the main constituents of essential oil obtained from Mutellina purpurea L., a plant with described antitubercular activity, to investigate their interactions with antibiotics against reference Mtb strains and multidrug-resistant clinical isolates...
January 15, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Davide Pisu, Roberta Provvedi, Dulce Mata Espinosa, Jorge Barrios Payan, Francesca Boldrin, Giorgio Palù, Rogelio Hernandez-Pando, Riccardo Manganelli
The emergence and spread of drug-resistant Mycobacterium tuberculosis strains possibly threaten our ability to treat this disease in the future. Even though two new antitubercular drugs have recently been introduced, there is still the need to design new molecules whose mechanisms of action could reduce the length of treatment. We show that two alternative sigma factors of M. tuberculosis (SigE and SigB) have a major role in determining the level of basal resistance to several drugs and the amount of persisters surviving long-duration drug treatment...
December 2017: Antimicrobial Agents and Chemotherapy
Weizhen Xu, Michael A DeJesus, Nadine Rücker, Curtis A Engelhart, Meredith G Wright, Claire Healy, Kan Lin, Ruojun Wang, Sae Woong Park, Thomas R Ioerger, Dirk Schnappinger, Sabine Ehrt
Chemotherapy for tuberculosis (TB) is lengthy and could benefit from synergistic adjuvant therapeutics that enhance current and novel drug regimens. To identify genetic determinants of intrinsic antibiotic susceptibility in Mycobacterium tuberculosis , we applied a chemical genetic interaction (CGI) profiling approach. We screened a saturated transposon mutant library and identified mutants that exhibit altered fitness in the presence of partially inhibitory concentrations of rifampin, ethambutol, isoniazid, vancomycin, and meropenem, antibiotics with diverse mechanisms of action...
December 2017: Antimicrobial Agents and Chemotherapy
Nicholas Zareifopoulos, George Panayiotakopoulos
Antimicrobial drugs used in clinical practice are selected on the basis of their selective toxicity against bacterial cells. However, all exhibit multiple offsite interactions with eukaryotic cell structures, resulting in adverse reactions during antimicrobial pharmacotherapy. A multitude of these side effects involve the nervous system as antimicrobials at clinically relevant concentrations seem to interact with many of the same molecules usually implicated in the action of psychotropic drugs. The importance of such events cannot be overstated, as the misdiagnosis of an adverse drug reaction as a symptom of a primary psychiatric or neurological disorder entails great suffering for the patient affected as well as significant costs for the healthcare system...
May 2017: Clinical Drug Investigation
Karin Schubert, Boris Sieger, Fabian Meyer, Giacomo Giacomelli, Kati Böhm, Angela Rieblinger, Laura Lindenthal, Nadja Sachs, Gerhard Wanner, Marc Bramkamp
Members of the genus Mycobacterium are the most prevalent cause of infectious diseases. Mycobacteria have a complex cell envelope containing a peptidoglycan layer and an additional arabinogalactan polymer to which a mycolic acid bilayer is linked; this complex, multilayered cell wall composition (mAGP) is conserved among all CMN group bacteria. The arabinogalactan and mycolic acid synthesis pathways constitute effective drug targets for tuberculosis treatment. Ethambutol (EMB), a classical antituberculosis drug, inhibits the synthesis of the arabinose polymer...
February 7, 2017: MBio
Vikrant S Rajput, Rukmankesh Mehra, Sanjay Kumar, Amit Nargotra, Parvinder Pal Singh, Inshad Ali Khan
Shikimate kinase of Mycobacterium tuberculosis is involved in the biosynthesis of aromatic amino acids through shikimate pathway. The enzyme is essential for the survival of M. tuberculosis and is absent from mammals, thus providing an excellent opportunity for identifying new chemical entities to combat tuberculosis with a novel mechanism of action. In this study, an antitubercular library of 1000 compounds was screened against M. tuberculosis shikimate kinase (MtSK). This effort led to the identification of 20 inhibitors, among which five promising leads exhibited half maximal inhibitory concentration (IC50) values below 10 μM...
June 2016: Applied Microbiology and Biotechnology
Robert P Baughman, Jan C Grutters
About half of patients with sarcoidosis will need systemic therapy for their disease. Oral glucocorticoids are the standard first-line treatment for sarcoidosis. With time, patients might develop substantial morbidity from long-term use of high doses of these drugs. We propose a step-wise approach to the management of pulmonary disease in sarcoidosis and provide details about how and when to use alternatives to glucocorticoids. The antimetabolites, such as methotrexate, azathioprine, leflunomide, and mycophenolate, are often used as alternatives to steroids...
October 2015: Lancet Respiratory Medicine
Sumit Chakraborty, Kyu Y Rhee
Modern tuberculosis (TB) chemotherapy is widely viewed as a crowning triumph of anti-infectives research. However, only one new TB drug has entered clinical practice in the past 40 years while drug resistance threatens to further destabilize the pandemic. Here, we review a brief history of TB drug development, focusing on the evolution of mechanism(s)-of-action studies and key conceptual barriers to rational, mechanism-based drugs.
April 15, 2015: Cold Spring Harbor Perspectives in Medicine
Yangzhe Wu, Ronald C Sims, Anhong Zhou
Dynamic nanomechanics and nanostructures of dividing and anti-mycobacterial drug treated mycobacterium remain to be fully elucidated. Atomic force microscopy (AFM) is a promising nanotechnology tool for characterization of these dynamic alterations, especially at the single cell level. In this work, single dividing mycobacterium JLS (M.JLS) before and after anti-mycobacterial drug (ethambutol, EMB) treatment was in situ quantitatively analyzed, suggesting that nanomechanics would be referred as a sensitive indicator for evaluating efficacy of anti-mycobacterial drugs...
September 28, 2014: Physical Chemistry Chemical Physics: PCCP
Ramona Danac, Ionel I Mangalagiu
Three classes of fused bipyridine heterocycles were designed, synthesized and evaluated for their antimycobacterial activities. The method for preparation of fused bipyridine derivatives is straight and efficient. The primary antimycobacterial screening reveals that mono-indolizine mono-salts are displaying potency superior to the second-line antitubercular drugs Cycloserine and Pyrimethamine and, equal as the first line anti-TB Ethambutol. The data from Cycle-2 screening assay (MIC, MBC, LORA, intracellular (macrophage) drug screening, and MTT cell proliferation) confirm the promising anti-TB results from Cycle-1 for mono-indolizine mono-salts...
March 3, 2014: European Journal of Medicinal Chemistry
Anthony Roylance, John Mosley, Mohideen Jameel, Axel Sylvan, Virginie Walker
INTRODUCTION: Intravesical BCG-instillation for bladder cancer is considered safe but is not without risk. While most side-effects are localised and self-limiting, the development of secondary vascular pathology is a rare but significant complication. PRESENTATION OF CASE: A 77-year-old male presented with a mycotic abdominal aortic aneurysm and associated aorto-enteric fistula 18 months after receiving intravesical BCG-instillations for early stage transitional cell carcinoma...
2013: International Journal of Surgery Case Reports
Ruiru Shi, Isamu Sugawara
Mycobacterium tuberculosis, the causative agent of tuberculosis, is a tenacious and remarkably successful pathogen that has latently infected one third of the world's population, according to the World Health Organization (WHO) statistics. It is anticipated that 10% of these infected individuals will develop active tuberculosis at some point in their lifetime. The long-term use of the current drug regimen, the emergence of drug-resistant strains, and HIV co-infection have resulted in a resurgence of research efforts to address the urgent need for new anti-tuberculosis drugs...
June 2010: Tohoku Journal of Experimental Medicine
Helen L Birch, Luke J Alderwick, Ben J Appelmelk, Janneke Maaskant, Apoorva Bhatt, Albel Singh, Jerome Nigou, Lothar Eggeling, Jeroen Geurtsen, Gurdyal S Besra
Maintenance of cell-wall integrity in Mycobacterium tuberculosis is essential and is the target of several antitubercular drugs. For example, ethambutol targets arabinogalactan and lipoarabinomannan (LAM) biosynthesis through the inhibition of several arabinofuranosyltransferases. Apart from their role in cell-wall integrity, mycobacterial LAMs also exhibit important immunomodulatory activities. Here we report the isolation and detailed structural characterization of a unique LAM molecule derived from Mycobacterium smegmatis deficient in the arabinofuranosyltransferase AftC (AftC-LAM)...
February 9, 2010: Proceedings of the National Academy of Sciences of the United States of America
Giovanna Riccardi, Maria Rosalia Pasca, Silvia Buroni
TB is still a global health problem. The selection and spread of multidrug-resistant and extensively drug-resistant Mycobacterium tuberculosis strains represents a threat for global TB control. The reappearance of TB has driven an increased interest in understanding the mechanisms of drug action and drug resistance, which could provide a significant contribution in the development of new antimicrobials. In this article, the authors describe the mode of action and the resistance mechanisms of the principal first- and second-line antitubercular agents, namely isoniazid, ethionamide, ethambutol, D-cycloserine, rifamycins, fluoroquinolones, streptomycin, linezolid and pyrazinamide...
June 2009: Future Microbiology
R E Hasenbosch, J W C Alffenaar, S A Koopmans, J G W Kosterink, T S van der Werf, R van Altena
BACKGROUND: Ethambutol (EMB) is one of the first-line drugs in the treatment against tuberculosis (TB). Side-effects are infrequent, but its main adverse effect, optical neuropathy, has long been recognised. The mechanisms of action and predisposing factors have not yet been fully understood. METHOD: We conducted a retrospective study (1992--2007) in an attempt to find predisposing factors for optical neuropathy. RESULTS: Visual disturbance was reported in 1...
August 2008: International Journal of Tuberculosis and Lung Disease
Veemal Bhowruth, Luke J Alderwick, Alistair K Brown, Apoorva Bhatt, Gurdyal S Besra
In spite of effective antibiotics to treat TB (tuberculosis) since the early 1960s, we enter the new millennium with TB currently the leading cause of death from a single infectious agent, killing more than 3 million people worldwide each year. Thus an understanding of drug-resistance mechanisms, the immunobiology of cell wall components to elucidate host-pathogen interactions and the discovery of new drug targets are now required for the treatment of TB. Above the plasma membrane is a classical chemotype IV peptidoglycan to which is attached the macromolecular structure, mycolyl-arabinogalactan via a unique diglycosylphosphoryl bridge...
August 2008: Biochemical Society Transactions
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