Challenges in Drug Discovery against Tuberculosis (original) (raw)

Attack on the Scourge of Tuberculosis: Patented Drug Targets

Recent Patents on Anti-Infective Drug Discovery, 2006

Tuberculosis is one of the most devastating bacterial diseases, with increasing rates of morbidity and mortality, despite the presence of effective chemotherapy and Bacillus-Calmette-Guerin (BCG) vaccine. The success of Mycobacterium tuberculosis lies in its ability to spread by aerosol droplets, evade the host immune system and to persist in pulmonary granulomas. The advancement in the field of molecular and cellular microbiology and the availability of transcriptome and proteome data of M. tuberculosis have aided in understanding the pathogenesis of this organism for developing more effective drugs. The current strategy of drug design is to identify gene products, which are essential for survival and virulence. To date, several gene products of mycobacteria, ranging from proteins involved in cell wall synthesis to energy generation and from entry into host to persistence, have been shown to be essential for the survival or virulence of M. tuberculosis. These proteins and their associated pathways are considered as promising drug targets against M. tuberculosis and several of these have been patent protected. Herein, we enlist drug targets against M. tuberculosis for which patents have been filed and issued during the last ten years. The significance of these drug targets in the development of drug is also discussed. This review presents a comprehensive account of the pivotal information for drug discovery and drug design to all researchers involved in tuberculosis research.

Multitarget Drug Discovery for Tuberculosis and Other Infectious Diseases

Journal of Medicinal Chemistry, 2014

We report the discovery of a series of new drug leads that have potent activity against Mycobacterium tuberculosis as well as against other bacteria, fungi, and a malaria parasite. The compounds are analogues of the new tuberculosis (TB) drug SQ109 (1), which has been reported to act by inhibiting a transporter called MmpL3, involved in cell wall biosynthesis. We show that 1 and the new compounds also target enzymes involved in menaquinone biosynthesis and electron transport, inhibiting respiration and ATP biosynthesis, and are uncouplers, collapsing the pH gradient and membrane potential used to power transporters. The result of such multitarget inhibition is potent inhibition of TB cell growth, as well as very low rates of spontaneous drug resistance. Several targets are absent in humans but are present in other bacteria, as well as in malaria parasites, whose growth is also inhibited.

Novel targets for tuberculosis drug discovery

Current opinion in pharmacology, 2006

Since the determination of the Mycobacterium tuberculosis genome sequence, various groups have used the genomic information to identify and validate targets as the basis for the development of new anti-tuberculosis agents. Validation might include many components: demonstration of the biochemical activity of the enzyme, determination of its crystal structure in complex with an inhibitor or a substrate, confirmation of essentiality, and the identification of potent growth inhibitors either in vitro or in an infection model. If novel target validation and subsequent inhibition are matched by an improved understanding of disease biology, then new antibiotics could have the potential to shorten the duration of therapy, prevent resistance development and eliminate latent disease.

Challenging the Drug-Likeness Dogma for New Drug Discovery in Tuberculosis

Frontiers in Microbiology, 2018

The emergence of multi-and extensively drug resistant tuberculosis worldwide poses a great threat to human health and highlight the need to discover and develop new, effective and inexpensive antituberculosis agents. High-throughput screening assays against well-validated drug targets and structure based drug design have been employed to discover new lead compounds. However, the great majority fail to demonstrate any antimycobacterial activity when tested against Mycobacterium tuberculosis in whole-cell screening assays. This is mainly due to some of the intrinsic properties of the bacilli, such as the extremely low permeability of its cell wall, slow growth, drug resistance, drug tolerance, and persistence. In this sense, understanding the pathways involved in M. tuberculosis drug tolerance, persistence, and pathogenesis, may reveal new approaches for drug development. Moreover, the need for compounds presenting a novel mode of action is of utmost importance due to the emergence of resistance not only to the currently used antituberculosis agents, but also to those in the pipeline. Cheminformatics studies have shown that drugs endowed with antituberculosis activity have the peculiarity of being more lipophilic than many other antibacterials, likely because this leads to improved cell penetration through the extremely waxy mycobacterial cell wall. Moreover, the interaction of the lipophilic moiety with the membrane alters its stability and functional integrity due to the disruption of the proton motive force, resulting in cell death. When a ligand-based medicinal chemistry campaign is ongoing, it is always difficult to predict whether a chemical modification or a functional group would be suitable for improving the activity. Nevertheless, in the "instruction manual" of medicinal chemists, certain functional groups or certain physicochemical characteristics (i.e., high lipophilicity) are considered red flags to look out for in order to safeguard drug-likeness and avoid attritions in the drug discovery process. In this review, we describe how antituberculosis compounds challenge established rules such as the Lipinski's "rule of five" and how medicinal chemistry for antituberculosis compounds must be thought beyond such dogmatic schemes.

Challenges in the development of drugs for the treatment of tuberculosis

The Brazilian Journal of Infectious Diseases, 2013

Tuberculosis infection is a serious human health threat and the early 21st century has seen a remarkable increase in global tuberculosis activity. The pathogen responsible for tuberculosis is Mycobacterium tuberculosis, which adopts diverse strategies in order to survive in a variety of host lesions. These survival mechanisms make the pathogen resistant to currently available drugs, a major contributing factor in the failure to control the spread of tuberculosis. Multiple drugs are available for clinical use and several potential compounds are being screened, synthesized, or evaluated in preclinical or clinical studies. Lasting and effective achievements in the development of anti-tuberculosis drugs will depend largely on the proper understanding of the complex interactions between the pathogen and its human host. Ample evidence exists to explain the characteristics of tuberculosis. In this study, we highlighted the challenges for the development of novel drugs with potent bacteriostatic or bactericidal activity, which reduce the minimum time required to cure tuberculosis infection. (Y.S. Lee). exceeding 5% per year. 1 However, surveillance and mathematical modeling suggests that the total TB incidence per capita is falling at an estimated 1% per year, a finding that indicates that the global incidence rate will decrease by 2015. However, the world's population is growing at about 2% per year, and thus the total number of new TB cases remains on the rise. 2 This finding reveals the relative failure of the existing management strategies for TB and the inadequate effectiveness of public health systems, mainly in underdeveloped countries. In spite of the availability of anti-TB drugs developed over the last five decades, one-third of the world's population retains a 1413-8670/$ -see front matter

2018 - Challenging the Drug-Likeness Dogma for New Drug Discovery in Tuberculosis

Fronteirs in Microbiology, 2018

The emergence of multi-and extensively drug resistant tuberculosis worldwide poses a great threat to human health and highlight the need to discover and develop new, effective and inexpensive antituberculosis agents. High-throughput screening assays against well-validated drug targets and structure based drug design have been employed to discover new lead compounds. However, the great majority fail to demonstrate any antimycobacterial activity when tested against Mycobacterium tuberculosis in whole-cell screening assays. This is mainly due to some of the intrinsic properties of the bacilli, such as the extremely low permeability of its cell wall, slow growth, drug resistance, drug tolerance, and persistence. In this sense, understanding the pathways involved in M. tuberculosis drug tolerance, persistence, and pathogenesis, may reveal new approaches for drug development. Moreover, the need for compounds presenting a novel mode of action is of utmost importance due to the emergence of resistance not only to the currently used antituberculosis agents, but also to those in the pipeline. Cheminformatics studies have shown that drugs endowed with antituberculosis activity have the peculiarity of being more lipophilic than many other antibacterials, likely because this leads to improved cell penetration through the extremely waxy mycobacterial cell wall. Moreover, the interaction of the lipophilic moiety with the membrane alters its stability and functional integrity due to the disruption of the proton motive force, resulting in cell death. When a ligand-based medicinal chemistry campaign is ongoing, it is always difficult to predict whether a chemical modification or a functional group would be suitable for improving the activity. Nevertheless, in the "instruction manual" of medicinal chemists, certain functional groups or certain physicochemical characteristics (i.e., high lipophilicity) are considered red flags to look out for in order to safeguard drug-likeness and avoid attritions in the drug discovery process. In this review, we describe how antituberculosis compounds challenge established rules such as the Lipinski's "rule of five" and how medicinal chemistry for antituberculosis compounds must be thought beyond such dogmatic schemes.

Recent Progress and Challenges for Drug-Resistant Tuberculosis Treatment

Pharmaceutics, 2021

Control of Mycobacterium tuberculosis infection continues to be an issue, particularly in countries with a high tuberculosis (TB) burden in the tropical and sub-tropical regions. The effort to reduce the catastrophic cost of TB with the WHO’s End TB Strategy in 2035 is still obstructed by the emergence of drug-resistant TB (DR-TB) cases as result of various mutations of the MTB strain. In the approach to combat DR-TB, several potential antitubercular agents were discovered as inhibitors for various existing and novel targets. Host-directed therapy and immunotherapy also gained attention as the drug-susceptibility level of the pathogen can be reduced due to the pathogen’s evolutionary dynamics. This review is focused on the current progress and challenges in DR-TB treatment. We briefly summarized antitubercular compounds that are under development and trials for both DR-TB drug candidates and host-directed therapy. We also highlighted several problems in DR-TB diagnosis, the treatmen...

How Mycobacterium tuberculosis drug resistance has shaped anti-tubercular drug discovery

Frontiers in Cellular and Infection Microbiology

Drug resistance is an increasing problem for the treatment of tuberculosis. The prevalence of clinical isolates with pre-existing resistance needs to be considered in any drug discovery program. Non-specific mechanisms of resistance such as increased efflux or decreased permeability need to be considered both in developing individual drug candidates and when designing novel regimens. We review a number of different approaches to develop new analogs and drug combinations or improve efficacy of existing drugs that may overcome or delay the appearance of clinical resistance. We also discuss the need to fully characterize mechanisms of resistance and cross- resistance to existing drugs to ensure that novel drugs will be clinically effective.