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CHAPTER'I SECTION A: Introduction to Tuberculosis and the drugs available for treatment. Chapter I, Section A History of Tuberculosis The truth, tuberculosis (TB) is a communicable disease caused by infection with the tubercle bacillus^ has been established by Robert Koch in the year 1882. Although humankind affliction with TB date backs to at least 5400" years, as evidenced by ancient mummified remains, genetic analysis of the Mycobacterium tuberculosis (Mtb) complex suggests that the common progenitor has infected our hominid ancestors since eons. Unabatedly Mtb has parasitized the human host over ages with its complicated and dynamic series of interaction. Nearly l/S'** of world's population has been infected with Mtb. Globally 9.2 million new cases and 1.7 million deaths occur every year albeit widespread vaccination and chemotherapy. While large chunk of new cases are reported from southeast Asia, the western pacific,^ 95% of all cases are from developing world. The incidence of HIV has refueled the mortality rate among TB cases as it promotes the infection to active clinical disease; While TB accelerates HIV viral replication causing progression to AIDS. Further worsening of the situation was the occurrence of an estimated 49000 new multi-drug resistant tuberculosis (MDR-TB) and extensively drug resistant tuberculosis PCDR-TB) cases every year according to a Global Drug Resistance Surveillance report.'' The Tubercle Bacillus The genus composition of fast growing soil microbes and slow growing pathogens including Mtb, Mycobacterium leprae, Mycobacterium bovis and Mycobacterium marinum constitute the rod shaped mycobacteria. With the exceptions of M microti and live- attenuated vaccine strain M bovis bacille Calmette-Guerin (BCG)' all of the slightly genetical variants of Mtb complex can cause disease in immuno­ competent humans, Mtb being the most important pathogen of Homo sapiens. The complex Mtb cell envelope consists of a plasma membrane, a cell wall, and a capsule-like outer layer (Fig. 1). The cell wall consists of, from innermost to outermost, peptidoglycan (PG), arabinogalactan (AG), mycolic acids (MA), and peripheral lipids. Lipoarabinomannan (LAM) is thought to be anchored in the plasma membrane and is also found in the capsule-like layer anchored in the MAs.* the thick complex Mtb cell wall renders the host ineffective to counter attack on the intra-phagosomal bacteria and 1 IPage Chapter I, Section A low permeability turns it insensitive to P-lactams and resistant to many other antibiotics. Moreover the retention of carbol ftjchsin stain is due to its unique cell wall mycolic acids. f •}G K ip 4Ah\ > ^ Figure 1: Schematic of Mycobacterial Cell Envelope^ (A) plasma membrane, (B) peptidoglycan, (C) arabinogalactan, (D) mannose-capped lipoarabinomannan, (E) plasma membrane- and cell envelope-associated proteins, (F) mycolic acids and (G) glycolipid surface molecules associated with the mycolic acids. Pathogenesis of disease When droplets (< 5 |am) housing one or more several Mtb bacteria were inhaled, they get deposited in the alveolar airspace while bigger ones are cleared by the pulmonary mucociliary system.^ Host alveolar macrophages phagocytize these bacteria. Bacterial replication within the membrane-bound phagocytic vesicles eventually overwhelms the macrophages leading to the rupture of the cells and the release of numerous bacilli. Both alveolar and monocyte-derived macrophages then take up these bacteria emigrating from blood stream. The bacterial spread commences approximately after 2 weeks when they begin to spill over from the primary lesion into surrounding tissue and then to regional lymph nodes. The infection remains latent for years or decades after primary exposure^ before reactivation in 5% of cases or takes several years to develop into primary progressive TB 2|Pa -e Chapter I, Section A stage in another 5% cases. But in a healthy individual it can be contained indefinitely or may be completely sterilized over time. In most cases progression to a disease state occurs in infants, the elderly, the malnourished, or those who are immuno-compromised by steroids, genetic predisposition or HIV. The gross cavitation occurring in the lung and necrotic tissue in severe post-primary disease can spill over into airways and the associated cough thereby spreads the bacteria within the lung of an individual and between an individual and his/her contacts. Diagnosis of active TB is based on symptomology, microscopic analysis of sputum stained to reveal acid-fast bacilli, sputum culture, DNA or RNA amplification assays, and/or chest radiograph. Signs and symptoms of TB include: night sweats, productive cough, bloody sputum, weight loss, and consolidated opacities (esp. apical) and/or upper lobe cavitation on lung X-ray. However, it should be noted that with severe immunodeficiencies such as HIV, patients with disseminated Mtb lung infection can display non-typical signs and symptoms mimicking other lung pathologies. Vaccines The live attenuated bacille Calmette- Guerin (BCG) is the only vaccine used to prevent TB ever since it has been invented by Robert Koch. Even though 90% of vaccinated people infected by Mtb never develop active TB despite lodging the viable tubercle bacilli in their tissue^"'^ lifelong, the apparent protective efficacy of BCG against TB ranged from 80% to nil'^ in large scale, placebo controlled and double-blinded clinical trials. Development of new vaccines to replace BCG demands a thorough understanding of the interaction of Mtb and human immune system. In order to be novel & truly protective they must generate more substantial and enduring immune responses than are seen in the course of natural infection. Chemotherapy The decade between 1941 and 1952 was a milestone in the history of medicine as it recorded the discovery of trio of drugs by three independent groups that could cure TB. Prior to discovery nearly 1 billion people have yielded to TB in the 2 centuries that spanned. The mortality rate was more than 50%'" due to uncomplicated pulmonar>' TB without antibiotics. In contrast the combination of ^-aminosalicylic acid (PAS) (2) 3 |Page Chapter I, Section A streptomycin (1) and isoniazid (3) could, if administered properly, cure TB completely and nearly universally (Fig. 2). Many effective drugs were identified later and treatment times were shortened. O p-Aitiinosalicylic acid (2) NH, OH OH Streptomycin (1) Isoniazid (3) Figure 2 After many trials'^ '^ drug treatment regimen were divided into two, first a two month long treatment with four drugs; either: streptomycin (1), isoniazid (3), rifampin (4) and pyrazinamide (5) or: isoniazid (3), rifampin (4), pyrazinamide (5) and ethambutol (EMB) (6). This is then followed by four months of isoniazid (3) and rifampin (4) (Fig. 3). 0^NH2 N' I^N Pyrazinamide (5) OH HN- -NH HO Rifampin (4) Ethambutol (6) Figure 3 4| Page Chapter /, Section A While these drugs represent a critical advance in our ability to treat TB, inadequate healthcare infrastructure, financial limitations, the longtime required for full treatment (6- 12 months) and the required number of drug doses, adverse effects, poor patient compliance contributing to appearance of multi-drug resistant (MDR) and extensively drug resistant (XDR) TB strains, the spread of HIV have prevented universal control of the disease. In light of these observations the desirable characteristics of new anti-TB drug include the followings: orally active, long acting, limited toxicity and inexpensive. It should act through novel mechanisms of action such that there is no cross-resistance with current drugs, and it can be active against both drug-sensitive and drug-resistant M. tuberculosis. The drug should preferably be bactericidal, and active against both actively dividing and nonreplicating persistent M. tuberculosis. Ideally, there should be presence of synergistic or additive effects with current drugs, absence of antagonism and no significant interactions with other drugs, in particular the antiretrovirals.'^ Recommendations from a recent survey based on clinical data''"'^^ suggest the use of at least five adequate anti TB drug regimen, the choice of which is driven by the actual or presumed (in view of past failed treatment) resistance characteristic of the strains of M tuberculosis considered. In order of preference they can be chosen from the following, (i) In any case, the first line agents still active on the patient: isoniazid (3), rifampin (4), pyrazinamide (5) and ethambutol (6). (ii) This is followed by the group of injectable drugs: streptomycin (1), kanamycin (7), amikacin (8), capreomycin (9) or viomycin/tuberactinomycin B (10) and the related tuberactinomycins A, N and O (Fig. 4). (iii) One of the many related antibacterial fluoroquinolones such as ciprofloxacin (11), ofloxacin (12a). levofloxacin (12b), or the more recent sparfloxacin (13), gatifloxacin (14), moxifloxacin (15) and sitafloxacin (16) should be included in the regimen. This class of antibiotics has now^'' been proven as indispensable treatment for MDR tuberculosis ' and some of these drugs may leads to shorter antituberculosis regimens.^^' (iv) Second line bacteriostatics, with established clinical efficacy,^' usually have more important side effects,^" they are/^-aminosalicylic acid (2), ethionamide (17a) (the propyl analogue prothionamide (17b) is also used) and cycloserine (18) (Fig. 5). 5|Page Chapter I, Section A HO HO,, OH H2N^V^"'0'S^0^Y"''O H HjN^ ^O OH OH OH NH2 r ^ ^ NH R = H: kanamycin (7) •^OH R =

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