**11. Conclusions**

reactive nitrogen species (RNS). The PafA protein does not share homology with any protein of known function [82]. Two specific proteasomeinhibitors, epoxomicin and a peptidicboronate prevented the growth of *M. tuberculosis* and turned out to be bactericidal during the recovery of the mycobacterium against exposure to RNS [81]. The operon that codifies for the proteasome was knocked out by using conditional gene silencing and it was proved that bacteria require it to survive during the chronic infection in mice and its silencing allowed the mouse to be free of the persistent infection [83]. Whereas the proteasome of the mycobacterium is essential for the infection of a host, it is not required to grow in a rich and aerated medium

Unlike other bacteria, *M. tuberculosis* possesses a unique defense system that relates the antioxidant and metabolic activities [81]. The system includes a peroxyredoxin, the C subunit of an alkylhydroperoxy-reductase (AhpC), a thioredoxin type protein (AhpD), dihydrolipoa‐ mideacyltransferase (DlaT), and lipoamide dehydrogenase (Lpd), and the four enzymes together work as peroxydases and peroxynitroreductases and peroxynitroreductasesdepend‐ ant of NADH [81]. The dual functionality of these enzymes is interesting as potential targets

Moreover,theDosRsystem,discovered15yearsago,regulates thedevelopmentofaformofnoneplicative survival without morphologic differentiation in *M. tuberculosis* (known as latency state).Thisstateofphysiologicquiescencemaintainedviablethemicroorganismforlongperiods of time, contributing with two key characteristicsof TB: the symptom-free latent infection state and the persistence of the active disease of the tubercular infection in spite of the prolonged therapy time. Due to the importance of the bacilli latency state in the pathophysiology and chemotherapy of the disease, researchers have set their interest in the DosR system. Drugs that attack the latent state of the bacterium not only would be the key for eradication of the latent

Traditionally, the focus of research is the evaluation of a single drugin extensive and costly trials. This process may take a lot of time and reduces the possibility of developing a combi‐ nation of new drugs that is effective. For this reason, a new approach to research has been led by the Critical Path to TB Drug Regimens (CPTR) organization created in March 2010 by the Bill & Melinda Gates Foundations, the Critical Path Institute, and the TB Alliance. This strategic partnership has the strength of reducing the time necessary to develop a new TB treatment scheme, as well as reducing significantly the research costs. This initiative has been endorsed by the US Food and Drug Administration and other regulatory entities, as well as the World

As a result of the 41st Union World Conference in Berlin, Germany, on November 2010, the TB Alliance announced the launch of the first clinical phase to test a new TB treatment scheme which expedites the treatment of patients. The combination of three drugs has been promising for the treatment of drug sensitive (DS-TB) and MDR-TB, thus changing the course of the TB

infection, but also shortening the time of treatment of active infection [84].

such as Middlebrook 7H9 broth [81].

350 Tuberculosis - Current Issues in Diagnosis and Management

for the development of anti-TB active principles.

**9. A new approach to research processes**

Health Organization [67].

Currently, devastating diseases in the world such as tuberculosis get the attention of author‐ ities with the aim of supporting breakthroughs which provide alternatives for their control.

The development of active principles against *M. tuberculosis* is nowadays a worldwide priority due to the appearance of strains resistant to medications used in current therapeutic schemes, thus existing the need to articulate in an expedite manner the basic research looking for new therapeutic choices, along with clinical research and its articulation with the industry in order to guarantee a quick production of novel alternatives which overcome the limitations of current treatment schemes.

The concern in many sectors devoted to tuberculosis control is that there are not sufficient alternatives that can join rapidly the treatment against tuberculosis, and they convey discour‐ aging estimations regarding the degree of resistance that each one of these molecules will have at the moment of entering the therapeutic scheme deduced from natural resistant bacilli. These justifications have promoted research around the world towards finding new molecules, based on investigations of natural sources such as plants, insects, marine microorganisms, synthetic molecules deduced from the modification or substitutions made on the structure of already existing molecules with the aim of potentiate their effect; or from new sources such as nanoparticles, computing studies, among many others.

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The results expected at the end of each process producing a new alternative of treatment against tuberculosis is that these drugs may shorten the duration of the current treatment, be active against resistant strains and non-replicative conditions of *M. tuberculosis* as well as not interfering with HIV antiretroviral therapy, reduce adverse side effects, and that it is of easy administration to facilitate the patient's compliance. For the management of tuberculosis as a public health event worldwide, these new drugs must be produced easily in large amounts; they must be stable under minimum storage conditions, and they must be of low cost so that all governments may guarantee access of all the diseased population.

For these expectations to become true in the short term, more basic and applied research is required to generate new ideas in the development of anti-tuberculosis drugs, as well as stronger financial support in research and greater commitment from the pharmaceutical industry and public health entities.
