Antitubercular Drugs Development: Recent Advances in Selected Therapeutic Targets and Rational Drug Design
Virgilio Bocanegra‐García, Abraham García, Jose Prisco, Isidro Palos, Gildardo River · InTech eBooks · 2011
Drug Development -A Case Study Based Insight into Modern Strategies 208months (Blumberg et al., 2006).If this treatment fails as a result of bacterial drug resistance or intolerance to one or more drugs, second-line drugs are used, such as para-aminosalicilate (PAS), kanamycin, fluoroquinolones, capreomycin, ethionamide and cycloserine.These are generally less effective or more toxic with serious side effects (Blumberg et al., 2006).This second-line treatment can also result ineffective since MDR-strains that exhibit resistance to these second-line drugs are currently on the rise (Zhang & Amzel, 2002) Treatment is also made quite difficult by the presence of metabolically silent, persistent or dormant bacteria within host lesions.These are not susceptible to the anti-mycobacterial drugs that usually kill growing but not persistent bacteria (Zhang, 2004).While there are many reasons for drug resistance, including prescription of inadequate regimens, an uncertain drug supply, and ineffective drugs, duration of lengthy treatments is one of the major contributors because some TB patients prematurely stop their therapy after an initial, rapid heath improvement, thereby favoring the emergence of drug-resistant strains (Cole & Alzari, 2007) Anti-TB drug targetsDespite the relative efficacy of current treatment, the various antibiotics that constitute firstand second-line drugs for TB therapy target only a small number of core metabolic processes such as Deoxyribonucleic acid (DNA) and Ribonucleic acid (RNA) synthesis, cell wall synthesis, and energy metabolism pathways (Zhang, 2005).New classes of drugs with additional drug targets that are difficult to overcome by mutation are urgently needed (Hansan et al., 2006).Desirable new targets should be involved in vital aspects of bacterial growth, metabolism and viability whose inactivation would lead to bacterial death or an inability to persist, thus therapy could be shortened and drug resistant strains could be eliminated or drastically reduced (Mdluli & Spigelman, 2006;Duncan, 2004).Moreover, targets involved in the pathogenesis of the disease process should also be considered for drug development (Zhang et al., 2006;Palomino et al., 2009).The discovery of the complete genome sequence of TB bacteria helped to identify several important drug targets (Cole et al., 1998).Various groups have used this genomic information to identify and validate targets as the basis for development of new Anti-TB agents.Besides, mycobacterial genetic tools, such as transposon mutagenesis, gene knockout, and gene transfer, greatly facilitate target identification. Cell wall biosynthesis related targetsCell wall biosynthesis is a particularly good source of molecular targets because the biosynthetic enzymes do not have homologues in the mammalian system (Mdluli & Spigelman, 2006).The cell wall of M. tuberculosis is very important for its survival within constrained conditions such as those inside of human macrophages.The biosynthesis of the cell wall components involves many important stages and different enzymes that are absent in mammals and could be attractive drug targets (Khasnobis et al., 2002;Brennan & Crick, 2007;Sarkar & Suresh, 2011).Recently, the 2C-methyl-D-erytrol 4-fosphate (MEP) pathway was found (Eoh et al., 2009) as a potential drug target since the end product of the pathway leads to the formation of isoprenoids, which are responsible for the synthesis of several cell wall components (Mahapatra et al., 2005;Anderson et al., 1972).Peptidoglycan biosynthesis is another source of potential drug targets.For instance, alanine racemase and D-Ala-D-Ala-ligase catalyze the first and second committed steps in bacterial www.intechopen.comAntitubercular Drugs Development: Recent Advances in Selected Therapeutic Targets and Rational Drug Design 209 peptidoglycan biosynthesis, and since these steps are essential for important polymers, they are good drug targets.Both alanine racemase and D-Ala-D-Ala ligase are inhibited by Dcycloserine, a second line anti-TB drug (Strych et al., 2001;Feng & Barletta, 2003).Another good drug target is the pyridoxal 5'-phosphate containing enzyme Alr that catalyzes the racemization of L-Alanine into D-Alanine, a major component in the biosynthesis of peptidoglycan (LeMagueres et al., 2005).Arabinogalactan biosynthesis, a novel arabionofuranosyl transferase that catalyzes the addition of the first key arabinofuranosyl redisude of the galactan core, is not sensitive to EMB, but is essential for viability (Sassetti et al., 2003).The ribosyltransferase that catalyzes the first committed step in the synthesis of decaprenyl-phosphoryl-D-arabinose, the lipid donor of mycobacterial d-arabinofuranosyl residues, has also recently been characterized and shown essential for growth (Huang et al., 2005)