**1. Introduction**

Tuberculosis (TB) is a contagious infectious disease caused byspecies belonging to the *Mycobac‐ terium tuberculosis* complex. At present, it is a re-emerging disease, due to co-infection with the Human Immunodeficiency Virus (HIV), but also to global bacterial resistance, and lack of adequate treatment in some places in the world. Approximately one third of the world's population is infected with *M. tuberculosis*, and out of these people, about 1.1 million people die every year of TB [1], making this disease the main cause of bacterial infectious death in adoles‐ cents and adults all around the world. In 2010 there was an estimation of 8.8 million incident cases and 12.0 million prevalent cases of TB worldwide. *M. tuberculosis* drug-resistant isolates haveappearedgivingorigintomultidrug-resistant(MDR)andextensivelydrug-resistant(XDR) strains. XDR-TB has been identified in every continent of the planet. By 2010, the World Health Organization (WHO) was notified of the existence of 53.018 cases of multi-drug resistant TB (MDR-TB) worldwide; figure that only represents 18% of the TB-MDR estimated cases among reported pulmonary TB cases around the world [1]. Currently, there is global alarm since the infection with these strains is cured only in 66% of MDR cases and in 60% of the XDR cases [2].

More than sixty years ago, the introduction of the first anti-TB drugs for the treatment of TB (streptomycin (STR), *p*-aminosalcylic acid (PAS), isoniazid (INH) and then later ethambutol (EMB) and rifampicin (RIF)) gave optimism to the medical community, and it was believed that the disease would be completely eradicated soon. After a 30-year halt of anti-TB drug Research & Development pipeline, the Global Alliance for TB Drug Development (TB Alliance) started to fill the gap between the existing chemotherapeutics and the clinical need. Despite the efforts carried out with candidates in clinical trials such as PA-824 and bedaquiline, there is an urgent need of in-depth medicinal chemistry discovery studies for assuring enough leads

© 2013 Guzman et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

and candidates feeding the pipeline within the next decade[3]. Emerging chemical entities must shorten the time of treatment, be potent and safe while effective facing resistant strains and non-replicative, latent forms, and not interfere in the antiretroviral therapy [4]. In this review, we explore why we require to work continuously on the development of novel anti-TB agents, the stages necessary for the development of new anti-TB agents, breakthroughs in the discovery of new active principles and targets, the preclinical and clinical development of drugs, as well as the new approaches for the search of anti-TB active principles.

Active principle (year of discovery)

> Rifampicin (1966)

Pyrazinamide

Ethambutol

Streptomycin (1944)

Kanamycin (1957)

Amikacin (1972)

Fluoroquinolones

Ethionamide

*p*-aminosalicilic acid (1946)

> Cycloserine (1952)

Second Line

Semisynthetic

(1952) Synthetic 490 pH 5.5

Semisynthetic

(1961) Synthetic 2.45 Aarabinogalactanbios

(1980s) Synthetic 0.6-1.4 DNA replication and

(1956) Synthetic 1.5 Mycolic acid

Prothionamide Synthetic 2.77 Mycolic acid

Synthetic 1.9-6.5

population stages listed below [9] and showed in Figure 1:

Natural 1.72 Protein synthesis

Natural 3.43 Protein synthesis

Natural <sup>245</sup> Peptidoglycan

**Table 1.** Reported MIC and molecular targets drugs of first and second-line drugs used in the treatment of TB [7].

Since the start of chemotherapeutic era, physicians have realized the slowness and difficulty of achieving effective cure. McDermott et al proved in 1956 that the *in vitro*efficacy of first-line TB drugsdo not correlate to their *in vivo* efficacy [5]. Cultures of *M. tuberculosis* in exponential growth are sterilized *in vitro* in a few days by firstline agents such as INH and RIF, while the same combination requires months to achieve the same result in host tissue. It has been stated that mycobacterial persistency is due to the physiologic heterogeneity of bacillus in the tissues, the existence of subpopulations with completely different rate-determining factors. Despite an urgent need for new therapies targeting persistent bacteria, our knowledge of bacterial metabolism throughout the course of infection remains rudimentary [8].Mitchison and colleagues proposed in 1979 that, in lesions, *M. tuberculosis*exists under at least four different

Source MIC (µM) Action mechanism Target site

inhibition

Breakage of transport membrane and energetic depletion

ynthesisinhibition

inhibition

inhibition

inhibition

biosynthesis inhibition

biosynthesis inhibition

Inhibition of thymidilate synthase and iron acquisition

synthesis inhibition

0.85-1.7 Protein synthesis

RNA polymerase β

Research and Development of New Drugs Against Tuberculosis

Membrane energy

Arabinosyltransferas

rRNA ribosomal

rRNA ribosomal

rRNA ribosomal

Enoylreductase

Enoylreductase

transcription inhibition DNA gyrase gyrA, gyrB

sub-unit rpoB

metabolism pncA

proteins S12 and 16S *rpsL, rrs*

proteins S12 and 16S *rpsL, rrs*

proteins S12 and 16S rpsL, rrs

Thymidilate synthase thyA

D-alanine racemase alrA,ddl

(InhA) inhA, etaA/ethA

(InhA) *inhA, etaA/ethA*

<sup>e</sup> embCAB

0.486 RNA synthesis

Genes involved in the resistance 333

http://dx.doi.org/10.5772/54278
