Tuberculosis Treatment: The Search For New Drugs

In this chapter will be highlight some important historical facts of tuberculosis treatment and drug development, such as theories, studies and treatment of TB between 17-20^th Century, historical aspects of TB drug discovery, side effects, fixed-dose combinations, causes of the resurgence of TB, AIDS, multi-drug-resistant tuberculosis (MDR TB) and extensive-drug- resistant (XDR).

To overcome the problems with available treatments, new drugs to treat TB are urgently required, specifically more potent therapies, with fewer side effects, to be used in shorter treatment regimens and to be employed to treat MDR TB and latent disease. Unfortunately, after the introduction of rifampin in the market (1966-1970), no new classes of anti-TB drugs have been developed in the last forty-three year, excepted by rifapentine, a very close analog of rifampin, which was introduced by the FDA in 1998 and more recently bedaquiline, a diarylquinoline approved by FDA for multidrugresistant tuberculosis in December 2012. In this context, different new initiatives have been created to obtain promising drug candidates. Considering that, this chapter will be highlights promising drugs in advanced clinical trials that may soon be introduced onto the market.

Nowadays, the evaluation of known drugs against different targets or diseases has become a new strategy in drug discovery. Many of known drugs have exhibited very good efficacy against TB and this methodology is very fruitful because PK-PD (Pharmacokinetic-pharmacodynamic), toxicity and preclinical studies are known for such drugs, which can be useful for conducting clinical trials directly. Fluoroquinolones are the best example, where moxifloxacin and, gatifloxacin used as antiinfective drugs are in advanced clinical trials against TB (Chapter 2). Known drugs exhibiting anti TB activity can also be used as a start point for chemical modifications in the search of new TB lead compounds. In this context several known drugs, such as antimalarial drugs, isoxyl, thiosemicarbazone, clofazimine, diclofenac, macrolide and thioridazine will be highlight in this chapter.

TB became again an important infectious disease worldwide in the mid- 1980´s, and several factors are responsible for this, such as AIDS epidemic, the advent of multidrug resistant strains (MDR), poor socioeconomic condition and immigration. Unfortunately, due to the disadvantages of the first and second line drugs, and the increase of MDR strains worldwide, nowadays we urgent need new drugs to improve the TB treatment or a tragedy can happen. Considering this problem, several actions have been made, and in 2000 it was established the Global Alliance for TB Drug Development (GATB; www.tballiance.org). In this context, GATB have been working in partnership with different kinds of organizations, such as academic institutions, government research laboratories, non-governmental organizations, pharmaceutical industries and contract research houses. Due to its important work, GATB have changed the perspective of TB drug discovery. Considering that, this chapter aims to highlight synthetic compounds from different chemical classes, which were evaluated against M. tuberculosis in the last fifteen years.

The antibiotic streptomycin was the first drug used to treat TB and illustrated well the important role of nature in the fight against diseases. For example, several natural products were discovered between 1940-60´s against Mycobacterium tuberculosis being used nowadays in TB treatment as second-line drugs. Due to the importance of nature in the past and the present for TB treatment and drug discovery, a lot of attention has been given to new anti-TB drugs based on natural products nowadays, especially against MDR and XDR-TB. Considering that, the aim of the present chapter is to highlight promising natural product candidates in clinical trials against TB.

Natural products represent an outstanding source of compounds able to play an important role in the treatment of several human diseases. For example, plants are an incredible source of bioactive compounds isolated from different species with an impressive structural diversity, representing a field of inspiration for the development of new drugs. The importance of natural products in drug discovery can be noted in the large number of drugs derived from plants available against different classes of disease. Due to the importance of the plants in drug discovery, several compounds have been isolated and evaluated from different species against Mycobacterium tuberculosis, which some of the most promising it will be described in this chapter.

For six decades, natural products have taken a central role in the discovery of new antimicrobial agents. The structural diversity of these compounds and its ability for interacting specifically with biological target molecules has laid an ideal foundation in the development of new drugs. The importance of fungus in TB treatment can be observed in several aminoglycosides isolated from different Streptomyces species, which are used as second line drug. Due to the fundamental importance of fungi in the past and present of TB treatment, several research groups isolated and evaluated a number of compounds from different fungal species against Mycobacterium tuberculosis, which will be described in this chapter.

The interest of marine natural products in the development of new drugs to treat tuberculosis began in the 1990s with compounds isolated and evaluated in both plant and animal sources becoming an important source of new anti-TB compounds that will be covered in this chapter.