**3. Why we need new active anti-TB agents?**

Whereas it is true that TB can be cured with the current active principles, treatment is complex and long, involving four drugs for two months and two drugs for four months more as a minimum.



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.

**treatment of TB**

332 Tuberculosis - Current Issues in Diagnosis and Management

minimum.

First Line

Active principle (year of discovery)

Isoniazid

**2. Targets and action mode of active principles currently used in the**

lones, STR, kanamycin (KAN)), and membrane energy metabolism inhibitors (PZA).

cure but fails to obtain a bacteriological cure [5].

(1952) Synthetic 0.182

**3. Why we need new active anti-TB agents?**

Current TB chemotherapy is based on the combination of four anti-TB drugs which inhibit the bacterial metabolism, particularly the cell wall synthesis [5]. During the therapy, the goal of this drug combination strategy is to prevent effectively the mutational events [6]. According to their actionmode,firstandsecondlineanti-TBdrugsaregroupedintocellwallinhibitors (INH,EMB, ethionamide (ETH), and cycloserine (DCS)), protein synthesis inhibitors (RIF, fluoroquino‐

Current chemotherapy principally inhibits cell processes such as cell wall biosynthesis and DNA replication, and they only turn to be active regarding bacteria in active growth [5]. This implies that the chemotherapeutic agents in use are efficient bactericides but are poor steri‐ lizers, not able to kill "dormant" *M. tuberculosis* which persists in macrophages after the death of the active bacteria [5]. RIF and PZAhave a partial sterilizing activity and they play an important role in the decrease of therapy from 18 to 6 months, even though there is a persistent population surviving these two agents. Consequently the current therapy ensures a clinical

Whereas it is true that TB can be cured with the current active principles, treatment is complex and long, involving four drugs for two months and two drugs for four months more as a

Source MIC (µM) Action mechanism Target site

Mycolic acids synthesis inhibition, multiple effects on DNA, lipids and carbohydrates

Enoylreductase

Genes involved in the resistance

(InhA) katG, inhA, ndh

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


system, and the bones [13]. It has been estimated that HIV infected patients are 100 times more likely to develop TB [14]. Although the studies support a decrease of mortality for TB patients after the introduction of antiretroviral therapy, evidence of the existence of interactions between Highly active antiretroviral therapy (HAART)and TB chemotherapy. HAAR is based on a combination therapynormally involving two reverse-transcriptase inhibitors and a noninhibitor [15]. P450 Cytochrometypicallymetabolizes reverse-transcriptase inhibitors,however this cytochrome is also induced by RIF. TB chemotherapy may reduce significantly the concentrations of anti-retroviral drugs which may lead to treatment failure or resistance. An increase of the nevirapine dose to compensate for this interaction increases the risk of toxic effects and hepatotoxicity in patients who already present a low body mass index and high level of CD4 lymphocytes [16]. Physicians prefer to avoid the concomitant use of nevirapine and RIF; consequently there is a clinical need for mycobactericidal agents devoid of P450

Research and Development of New Drugs Against Tuberculosis

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

335

Antibiotic discovery began in the early 1930s when different classes were discovered [17]. At the end of the 1950 decade, the combined regime was established and was thought to eradicate the disease completely. In the following thirty years after the introduction of the last first-line anti-TB drug, RIF, the regimen remained unchanged. The landscape changed in 1993 when the WHO declared TB a global health emergency [18]. Until recently, research in development of new anti-TB drugs was poor. These days, the TB Alliance has emerged as a non-profit organization promoting and funding anti-TB drug development by creating consortia over a defined project involving oftenbig pharmacompanies, institutes of research, and universities. Interest in drug discovery has placed on both phenotypic and target-based approaches to set in motion strong pipeline. With the joint effort of the Working Group on New TB Drugs, Stop TB Partnership and other societies.gatifloxacin, delamanib, PA824, rifapentine, sutezolid, SQ-109, bedaquiline and linezolid are candidatesin clinical trial [19]. There are other promising compounds (CPZEN-45, BTZ043, AZD5847, DC-159a and others), but a handful ofscientists believe that the gap is large and there is no certainty whether there will be a full new regimen

Neglected diseases affect mostly the poorest population on Earth, predominantly those who live in remote, rural areas, in depressed urban settings, or in regions of conflict. Together with malaria, leishmaniasis,filariasis and Chagas disease, TB makes part of the high impact neglected diseases, which unfortunately represent an insufficient market to attract enough investment on research by the pharma industry [20]. Whereas the most advanced societies have increased their life expectation thanks to technological development of medicine, in developing countries these diseases (some of which are preventable, treatable, and curable) still devastate the frailest populations. However, governments, multilateral organizations, and foundations spend billions of dollars in the procurement of treatments; and with the current situation of the disease, world health care organisms applaud recent efforts to develop new

anti-TB drugs, even though the panorama is not that promising yet [3,21].

catabolism.

**4. A 50-year wait**

in the next decade [3].

**Figure 1. Spectrum of** *M. tuberculosis***physiology.**Extent of variation of physiological cell subpopulations of M. tu‐ *berculosis* on an *in vivo* environment. Notice that first-line drugs mainly inhibit actively dividing bacteria, while there is not a single agent targeting the lower physiologically active stages.

During the initial chemotherapy phase (2 months), actively dividing bacilli rapidly die mostly because of INH bactericidal activity. Thereafter bacilli of low metabolic activity suffer from a slow death under the effects of RIF and PZA. There is evidence that persistentbacillarpopula‐ tion existing in the lesions usually determines the duration oftherapy [9]. Therefore efforts need to be made to target every physiological state of *M. tuberculosis* thus shortening the time of therapy and the appearance of drug resistance.

That brings us to the second reason why we need new anti-TB drugs. Drug resistance has emerged as a phantom from the dark, threatening today every corner of the world. RIFresistance often correlates to MDR category (resistant to INH and RIF). XDR *M. tuberculosis* is an MDR strain also resistant to any fluoroquinolone and at least one injectable agent. Prognosis is less favorable for patients harboring XDR-bacilly compared to patients with MDR, with five times higher risk of death, require longer hospitalization or treatment times. However it has been shown that within an aggressive treatment, XDR-TB patients have been successfully cured in 60% [10,11]. Treatment of M/XDR-TB usually takes more than two years, and requires the use of more toxic, less effective and more expensive drugs. In resource-limiting countries, supplies of second-line drugs cannot be guaranteed. In an attempt to improve the conditions for millions of patients, Jim Yong Kim and Paul Farmer from Partners in Health brought down the price of second-line drugs has by more than 80%. Unfortunately the latest reports from Italy, India and Iran, facing the extremely (XXDR) or totally (TDR) super-bug, have made imperious the essential necessity of new drugs targeting novel mechanisms of action [12].

TB infection in immune-compromisedpopulation leads tosevere cases,possibly affecting other parts of the body, such as the pleura, meninges, the lymphatic system, the genitourinary system, and the bones [13]. It has been estimated that HIV infected patients are 100 times more likely to develop TB [14]. Although the studies support a decrease of mortality for TB patients after the introduction of antiretroviral therapy, evidence of the existence of interactions between Highly active antiretroviral therapy (HAART)and TB chemotherapy. HAAR is based on a combination therapynormally involving two reverse-transcriptase inhibitors and a noninhibitor [15]. P450 Cytochrometypicallymetabolizes reverse-transcriptase inhibitors,however this cytochrome is also induced by RIF. TB chemotherapy may reduce significantly the concentrations of anti-retroviral drugs which may lead to treatment failure or resistance. An increase of the nevirapine dose to compensate for this interaction increases the risk of toxic effects and hepatotoxicity in patients who already present a low body mass index and high level of CD4 lymphocytes [16]. Physicians prefer to avoid the concomitant use of nevirapine and RIF; consequently there is a clinical need for mycobactericidal agents devoid of P450 catabolism.
