**4. A 50-year wait**

**1.** Bacteria in active growth, susceptible to INH.

334 Tuberculosis - Current Issues in Diagnosis and Management

not a single agent targeting the lower physiologically active stages.

of therapy and the appearance of drug resistance.

**2.** Bacteria with intermittent metabolism period, susceptible to RIF.

**3.** Low metabolic activity bacteria residing in acidic pH, susceptible to PZA.

**4.** "Dormant" or "persistent" bacteria, non susceptible to any current active principle.

**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

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

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 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 in the next decade [3].

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].
