UNDERSTANDING TUBERCULOSIS – NEW APPROACHES TO FIGHTING AGAINST DRUG RESISTANCE Edited by Pere-Joan Cardona Understanding Tuberculosis – New Approaches to Fighting Against Drug Resistance Edited by Pere-Joan Cardona Published by InTech Janeza Trdine 9, 51000 Rijeka, Croatia Copyright © 2012 InTech All chapters are Open Access distributed under the Creative Commons Attribution 3.0 license, which allows users to download, copy and build upon published articles even for commercial purposes, as long as the author and publisher are properly credited, which ensures maximum dissemination and a wider impact of our publications After this work has been published by InTech, authors have the right to republish it, in whole or part, in any publication of which they are the author, and to make other personal use of the work Any republication, referencing or personal use of the work must explicitly identify the original source As for readers, this license allows users to download, copy and build upon published chapters even for commercial purposes, as long as the author and publisher are properly credited, which ensures maximum dissemination and a wider impact of our publications Notice Statements and opinions expressed in the chapters are these of the individual contributors and not necessarily those of the editors or publisher No responsibility is accepted for the accuracy of information contained in the published chapters The publisher assumes no responsibility for any damage or injury to persons or property arising out of the use of any materials, instructions, methods or ideas contained in the book Publishing Process Manager Marija Radja Technical Editor Teodora Smiljanic Cover Designer InTech Design Team First published February, 2012 Printed in Croatia A free online edition of this book is available at www.intechopen.com Additional hard copies can be obtained from orders@intechweb.org Understanding Tuberculosis – New Approaches to Fighting Against Drug Resistance, Edited by Pere-Joan Cardona p cm ISBN 978-953-307-948-6 Contents Preface IX Part Chapter Strategies for New Drug Discovering Multi-Drug/Extensively Drug Resistant Tuberculosis (Mdr/Xdr-Tb): Renewed Global Battle Against Tuberculosis? Claude Kirimuhuzya Chapter Chemotherapeutic Strategies and Targets Against Resistant TB 33 Neeraj Shakya, Babita Agrawal and Rakesh Kumar Chapter A New Hope in TB Treatment: The Development of the Newest Drugs Ruiru Shi and Isamu Sugawara 93 Chapter In Search of El Dorado: Current Trends and Strategies in the Development of Novel Anti-Tubercular Drugs 107 Héctor R Morbidoni Chapter An Approach to the Search for New Drugs Against Tuberculosis 137 Fernando R Pavan, Daisy N Sato and Clarice Q.F Leite Chapter Antitubercular In Vitro Drug Discovery: Tools for Begin the Search 147 Juan Bueno Chapter New Antitubercular Drugs Designed by Molecular Modification 169 Jean Leandro dos Santos, Luiz Antonio Dutra, Thais Regina Ferreira de Melo and Chung Man Chin VI Contents Chapter Part Chapter The Cord Factor: Structure, Biosynthesis and Application in Drug Research – Achilles Heel of Mycobacterium tuberculosis? 187 Ayssar A Elamin, Matthias Stehr and Mahavir Singh New Drugs to Face Resistance 207 Old and New TB Drugs: Mechanisms of Action and Resistance 209 Anastasia S Kolyva and Petros C Karakousis Chapter 10 Pyrazinecarboxylic Acid Derivatives with Antimycobacterial Activity 233 Martin Doležal, Jan Zitko and Josef Jampílek Chapter 11 The Potential Therapeutic Usage of Dithiocarbamate Sugar Derivatives for Multi-Drug Resistant Tuberculosis 263 Takemasa Takii, Yasuhiro Horita, Ryuji Kuroishi, Taku Chiba, Mashami Mori, Tomohiro Hasegawa, Tastuya Ito, Tatsuaki Tagami, Tetsuya Ozeki, Saotomo Ito and Kikuo Onozaki Chapter 12 Fighting Against Resistant Strains: The Case of Benzothiazinones and Dinitrobenzamides Silvia Buroni, Giovanna Riccardi and Maria Rosalia Pasca Chapter 13 Quinolone Resistance in Tuberculosis Treatment: A Structural Overview 291 Claudine Mayer and Alexandra Aubry Chapter 14 Antimycobacterial Activity Some Different Lamiaceae Plant Extracts Containing Flavonoids and Other Phenolic Compounds 309 Tulin Askun, Gulendam Tumen, Fatih Satil, Seyma Modanlioglu and Onur Yalcin Chapter 15 Cinnamic Derivatives in Tuberculosis 337 Prithwiraj De, Damien Veau, Florence Bedos-Belval, Stefan Chassaing and Michel Baltas Chapter 16 Potential Use of I suffruticosa in Treatment of Tuberculosis with Immune System Activation 363 Camila Bernardes de Andrade Carli, Marcela Bassi Quilles, Danielle Cardoso Geraldo Maia, Clarice Q Fujimura Leite, Wagner Vilegas and Iracilda Z Carlos 273 Preface In 1957, a Streptomyces strain, the ME/83 (S.mediterranei), was isolated in the Lepetit Research Laboratories from a soil sample collected at a pine arboretum near Saint Raphaêl, France This drug was the base for the chemotherapy with Streptomicine, which demonstrated in 1980 to have a 100 per cent efficacy rate after being used together with two or three other drugs during the first two months of treatment in addition to an extra four month treatment combined with Isoniazid The euphoria generated by the success of this regimen lead to the idea that TB eradication would be possible by the year 2000 Thus, any further drug development against TB was stopped Unfortunately, the lack of an accurate administration of these drugs originated the irruption of the drug resistance in Mycobacterium tuberculosis Once the global emergency was declared in 1993, seeking out new drugs became urgent In this book, diverse authors focus on the development and the activity of the new drug families Dr Pere-Joan Cardona Institut Germans Trias i Pujol (IGTP) Catalunya, Spain 362 Understanding Tuberculosis – New Approaches to Fighting Against Drug Resistance Silas, J.H., Ramsay, L.E & Freestone, S (1982) Hydralazine Once Daily in Hypertension, British Medical Journal, Vol.284, No.6329, pp 1602-1604 ISSN 0959 8138 Tanachatchairatana, T., Bremner, J.B., Chokchaisiri, R & Suksamrarn, A (2008) Antimycobacterial Activity of Cinnamate-Based Esters of the Triterpenes Betulinic, Oleanolic and Ursolic Acids, Chemical & Pharmaceutical Bulletin, Vol.56, No.2, pp 194-198 ISSN 1347 5223 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13, pp 4314-4322, ISSN 1520 6904 Yoya, G K., Bedos-Belval, F., Constant, P., Duran, H., Daffé, M & Baltas M (2009) Synthesis and Evaluation of a Novel Series of Pseudo-Cinnamic Derivatives as Antituberculosis Agents, Bioorganic & Medicinal Chemistry Letters, Vol.19, No.2, pp 341-343, ISSN 0960-894X Zhang, Y., Broser, M & Rom, W.N (1994) Activation of the Interleukin-6 Gene by Mycobacterium tuberculosis or Lipopolysaccharide is Mediated by Nuclear Factors NF-IL6 and NF-kappa β, Proceedings of the National Academy of Science of the USA, Vol.91, No.6, pp 2225-2229, ISSN 0027 8424 16 Potential Use of I suffruticosa in Treatment of Tuberculosis with Immune System Activation Camila Bernardes de Andrade Carli1, Marcela Bassi Quilles1, Danielle Cardoso Geraldo Maia1, Clarice Q Fujimura Leite1, Wagner Vilegas2 and Iracilda Z Carlos1 1Departamento de Análises Clínicas e Departamento de Ciências, Unesp, R Expedicionários Brasil 1601, Araraquara, SP, 2Departamento de Ciências Biológicas, Unesp, Rodovia Araraquara-Jẳ, Araraquara, SP, 3Departamento de Química Orgânica, Unesp, R Prof Francisco Degni, Araraquara, SP, Brazil Introduction 1.1 Tuberculosis and immune system Mycobacterium tuberculosis is a serious threat to humankind, with over million cases of tuberculosis (TB) annually, killing almost millions of people per year around the world (WHO, 2008) Moreover, side effects from first-line anti-TB drugs can cause significant morbidity, and compromise treatment regimens for TB (Yee et al., 2003) Most healthy individuals are able to control TB infection with a vigorous immune response, halting the progression of the disease, but not necessarily eradicating the microorganism (McKinney, 2000) The bacterium resides within macrophages, allowing them to resist the antimicrobial effector mechanisms of the host (Raupach & Kaufmann 2001) Macrophages constitute one of the main phagocyte cells of the immunological system and they are the first cells involved in an immunological response Part of their effectiveness is due to the production of nitric oxide (NO), hydrogen peroxide (H2O2) and cytokines, as well as phagocytosis of strange particles (Allavena et al., 2008; Carlos et al., 2004; Keil, 1999) Thus, the elimination of tuberculosis bacillus is involved in the production of these effectors molecules from immune system The hydrogen peroxide, generated by macrophages in a reaction catalyzed by an NADPH oxidase, was the first identified effector molecule that mediated mycobacteriocidal effects of mononuclear phagocytes (Lopes et al., 2005; Walker & Lowrie, 1981) In spite of several studies have indicated significant M tuberculosis resistance to oxidative stress in vitro and in vivo, a recent study showed that H2O2 induced the complete sterilization of the cultures of M tuberculosis by 24 h, after the exposition to 50mM of H2O2 (Volskuill et al., 2011) 364 Understanding Tuberculosis – New Approaches to Fighting Against Drug Resistance NO formed by the action of the inducible form of nitric oxide synthase (iNOS) reacts with oxygen radical forming RNI NO and related RNI have been reported to possess antimycobacterial activity (Chan et al., 2004; Kwon, 1997) Although the role of NO in human tuberculosis remains unsettled evidence supporting its importance has come from a variety of areas (Nathan & Shiloh, 2000) including the demonstration that human granulomas contain iNOS, endothelial-NOS and nitrotyrosine, a compound whose accumulation indicates production of NO (Nathan, 2002) Additionally, the ability of human alveolar macrophages to kill M tuberculosis is dependent on the activity of iNOS and the human macrophages taken from healthy subjects latently infected with M tuberculosis produce NO controlling the growth of the bacteria (Yang et al., 2009) The presence of NO within human granulomas could contribute to host resistance since in vitro experiments demonstrate direct RNS-mediated bacteriostatic (Firmani & Riley, 2002; Ouellet et al., 2002; Voskuil et al., 2003) and bactericidal activity (Nathan, 2002) Mice deficient in both phox and iNOS are much more susceptible to M tuberculosis infection than either mutant alone which would indicate that RNS and ROS protect the host in a partially redundant fashion (Shiloh & Nathan, 2000; Volskuill et al., 2011) TNF-α is a cytokine that plays multiple roles in immune and pathologic responses in tuberculosis, also required for acute infection control (Babbar et al., 2006; Flynn et al., 1995; Palladino et al., 2003) The pro-inflammatory cytokine TNF-α produced by activated macrophages is a central contributor to the immune response against M tuberculosis (Flynn, 1986; Marino et al., 2007 ) The role of TNF is of clinical interest due to the association of anti-inflammatory TNF-α blocking drugs with reactivation of latent TB in humans (Keane et al., 2001; Wintrop,2006) This cytokine has multiple immunological functions during infection with M tuberculosis: It has a direct role in immune cell recruitment via upregulation of endothelial adhesion molecules (Zhou, et al., 2007) facilitating transendothelial migration of immune cells to the site of infection TNF-α regulates production of chemokines by macrophages (Algood et al., 2006; Roach et al., 2002); chemokines can further induce transendothelial migration and coordinate recruitment of immune cells within the tissues TNF-α activates macrophages in conjunction with the cytokine IFN-γ (Flesch & Kaufmann 1986; Roock et al., 1986; Carlos et al., 2009) such activated macrophages can kill intracellular mycobacteria TNF-α can also induce necrotic or apoptotic cell death in macrophages (Laster et al., 1988) that is promoted by TB infection (Keane, et al., 2001) 1.2 Plant with antimycobacterial and immunostimulating activity With proposal to stimulate the immune system, some plants can be used in collaboration with the standards drugs for the treatment of tuberculosis Moreover, there are a lot of plants that can be able to presenting an antimycobacterial activity It is possible to assign this effect to the substances contained in its structure which are responsible for protecting the plant structure from aggressive agents in what concerns the active ingredients of plants with an antimicrobial character Most of these substances are part of the secondary metabolites which consist of substances produced by plants which are not vital and involved in metabolic mechanisms Flavonoids, tannins, terpenes, alkaloids, phenolic compounds, etc are examples of secondary metabolites Thereby, many of these compounds protect the vegetal structure against external aggression such as insects, solar radiation, fungi, bacteria and viruses (Heldt, 1997) Potential Use of I suffruticosa in Treatment of Tuberculosis with Immune System Activation 365 Terpenoids are known as natural insecticides This class also includes limonoids, limonene and myrcene which plays an important role in the protection of the plants against insects Some terpenoids have already been tested and have manifested an activity against mycobacterium (Cantrell et al., 2001) Terpenes are composed by basic units of active isoprene isopentenilpirofosfatou, and originate triterpenes and sesquiterpenes previously mentioned in literature as substances with bacterial features (Januario et al., 2002; Pietro et al., 2000) Essential oils such as geraniol, citronellol, cineole and other genus Eucalyptus L'Herit, are recognized as bactericide (Hinou et al 1989; Leite et al., 1998) The alkaloid obtained from extracts of leaves of A Vasic, vasicine acetate and 2-acetyl benzyl amine showed promising antimycobacterial activities in several strains of M tuberculosis (Gupta et al., 2010) The endophytic fungi are microorganisms capable of producing potentially bioactive metabolites These molecules may have hormonal, antibiotic or antitumor activities and other biological functions of enormous industrial and biotechnology interest Tan and Zou (2001) examined the diversity of metabolites from isolated endophytic fungi and reported the isolation of substances belonging to different structural groups such as steroids, xanthones, phenols, isocoumarins, alkaloids, quinones, furandionas, terpenoids, peptides, cytochalasins and aliphatic compounds 3-D citosporona, fomopsolida and the acid “coletótricose” stand out for their antibacterial activity shown in several studies (Brady et al 2000; Zou et al., 2000) Considering the importance of immunomodulation in the treatment of tuberculosis, the activation of some components of the immune system is a great advantage when it is associated with the bacterial/bacteriostatic activity of the plants As examples of substances which have immunostimulant and antimicrobial actvities associated, the lectin derived from Synadenium carinatum has an important stimulatory activity of granulocytes and NK cells It is also able to stimulate the expression of TNF-α, IL-1 and iNOS in murine peritoneal macrophages (Cardoso, 2006) This activity is due, partially, to the presence of tannins This class of secondary metabolites can stimulate the production of IL-1 and TNF-α in macrophages as well as having a significant antimicrobial activity with MIC