Editorial

3 pages, 175 KiB

Open AccessEditorial

Editorial on Special Issue “Tuberculosis Drug Discovery and Development 2019”

by Claudia Sala, Laurent Roberto Chiarelli and Giovanna Riccardi

Appl. Sci. 2020, 10(17), 6069; https://doi.org/10.3390/app10176069 - 02 Sep 2020

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Mycobacterium tuberculosis, the etiological agent of human tuberculosis (TB), represents a global challenge to human health since it is the main cause of death by an infectious disease worldwide [...] Full article

(This article belongs to the Special Issue Tuberculosis Drug Discovery and Development 2019)

2 pages, 162 KiB

Open AccessEditorial

Drugs and Vaccines Will Be Necessary to Control Tuberculosis

by Rino Rappuoli

Appl. Sci. 2020, 10(11), 4026; https://doi.org/10.3390/app10114026 - 10 Jun 2020

Cited by 1 | Viewed by 1781

Abstract

For most infectious diseases, vaccines are used to prevent infection and drugs are used for acute therapy and eradication of established infections [...] Full article

(This article belongs to the Special Issue Tuberculosis Drug Discovery and Development 2019)

Research

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10 pages, 2018 KiB

Open AccessArticle

A Physical Cure for Tuberculosis: Carlo Forlanini and the Invention of Therapeutic Pneumothorax

by Paolo Mazzarello

Appl. Sci. 2020, 10(9), 3138; https://doi.org/10.3390/app10093138 - 30 Apr 2020

Cited by 3 | Viewed by 7865

Abstract

Carlo Forlanini (1847–1918), a medical doctor professor at the universities of Turin and Pavia, was the inventor of artificial pneumothorax, a method that allowed a first significant victory in the long war of medicine against pulmonary tuberculosis. The article outlines a portrait of [...] Read more.

Carlo Forlanini (1847–1918), a medical doctor professor at the universities of Turin and Pavia, was the inventor of artificial pneumothorax, a method that allowed a first significant victory in the long war of medicine against pulmonary tuberculosis. The article outlines a portrait of this important clinician and focuses on the therapeutic innovation he introduced for the treatment of this infectious disease. Full article

(This article belongs to the Special Issue Tuberculosis Drug Discovery and Development 2019)

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Review

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19 pages, 2888 KiB

Open AccessReview

Two Decades of TB Drug Discovery Efforts—What Have We Learned?

by Balachandra Bandodkar, Radha Krishan Shandil, Jagadeesh Bhat and Tanjore S. Balganesh

Appl. Sci. 2020, 10(16), 5704; https://doi.org/10.3390/app10165704 - 17 Aug 2020

Cited by 13 | Viewed by 4131

Abstract

After several years of limited success, an effective regimen for the treatment of both drug-sensitive and multiple-drug-resistant tuberculosis is in place. However, this success is still incomplete, as we need several more novel combinations to treat extensively drug-resistant tuberculosis, as well newer emerging [...] Read more.

After several years of limited success, an effective regimen for the treatment of both drug-sensitive and multiple-drug-resistant tuberculosis is in place. However, this success is still incomplete, as we need several more novel combinations to treat extensively drug-resistant tuberculosis, as well newer emerging resistance. Additionally, the goal of a shortened therapy continues to evade us. A systematic analysis of the tuberculosis drug discovery approaches employed over the last two decades shows that the lead identification path has been largely influenced by the improved understanding of the biology of the pathogen Mycobacterium tuberculosis. Interestingly, the drug discovery efforts can be grouped into a few defined approaches that predominated over a period of time. This review delineates the key drivers during each of these periods. While doing so, the author’s experiences at AstraZeneca R&D, Bangalore, India, on the discovery of new antimycobacterial candidate drugs are used to exemplify the concept. Finally, the review also discusses the value of validated targets, promiscuous targets, the current anti-TB pipeline, the gaps in it, and the possible way forward. Full article

(This article belongs to the Special Issue Tuberculosis Drug Discovery and Development 2019)

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20 pages, 640 KiB

Open AccessFeature PaperReview

Multi-Omics Technologies Applied to Tuberculosis Drug Discovery

by Aaron Goff, Daire Cantillon, Leticia Muraro Wildner and Simon J Waddell

Appl. Sci. 2020, 10(13), 4629; https://doi.org/10.3390/app10134629 - 03 Jul 2020

Cited by 16 | Viewed by 5087

Abstract

Multi-omics strategies are indispensable tools in the search for new anti-tuberculosis drugs. Omics methodologies, where the ensemble of a class of biological molecules are measured and evaluated together, enable drug discovery programs to answer two fundamental questions. Firstly, in a discovery biology approach, [...] Read more.

Multi-omics strategies are indispensable tools in the search for new anti-tuberculosis drugs. Omics methodologies, where the ensemble of a class of biological molecules are measured and evaluated together, enable drug discovery programs to answer two fundamental questions. Firstly, in a discovery biology approach, to find new targets in druggable pathways for target-based investigation, advancing from target to lead compound. Secondly, in a discovery chemistry approach, to identify the mode of action of lead compounds derived from high-throughput screens, progressing from compound to target. The advantage of multi-omics methodologies in both of these settings is that omics approaches are unsupervised and unbiased to a priori hypotheses, making omics useful tools to confirm drug action, reveal new insights into compound activity, and discover new avenues for inquiry. This review summarizes the application of Mycobacterium tuberculosis omics technologies to the early stages of tuberculosis antimicrobial drug discovery. Full article

(This article belongs to the Special Issue Tuberculosis Drug Discovery and Development 2019)

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19 pages, 5747 KiB

Open AccessReview

Structure-Based Drug Design for Tuberculosis: Challenges Still Ahead

by Eduardo M. Bruch, Stéphanie Petrella and Marco Bellinzoni

Appl. Sci. 2020, 10(12), 4248; https://doi.org/10.3390/app10124248 - 20 Jun 2020

Cited by 8 | Viewed by 3948

Abstract

Structure-based and computer-aided drug design approaches are commonly considered to have been successful in the fields of cancer and antiviral drug discovery but not as much for antibacterial drug development. The search for novel anti-tuberculosis agents is indeed an emblematic example of this [...] Read more.

Structure-based and computer-aided drug design approaches are commonly considered to have been successful in the fields of cancer and antiviral drug discovery but not as much for antibacterial drug development. The search for novel anti-tuberculosis agents is indeed an emblematic example of this trend. Although huge efforts, by consortiums and groups worldwide, dramatically increased the structural coverage of the Mycobacterium tuberculosis proteome, the vast majority of candidate drugs included in clinical trials during the last decade were issued from phenotypic screenings on whole mycobacterial cells. We developed here three selected case studies, i.e., the serine/threonine (Ser/Thr) kinases—protein kinase (Pkn) B and PknG, considered as very promising targets for a long time, and the DNA gyrase of M. tuberculosis, a well-known, pharmacologically validated target. We illustrated some of the challenges that rational, target-based drug discovery programs in tuberculosis (TB) still have to face, and, finally, discussed the perspectives opened by the recent, methodological developments in structural biology and integrative techniques. Full article

(This article belongs to the Special Issue Tuberculosis Drug Discovery and Development 2019)

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18 pages, 748 KiB

Open AccessReview

Post-Tuberculosis (TB) Treatment: The Role of Surgery and Rehabilitation

by Dina Visca, Simon Tiberi, Rosella Centis, Lia D’Ambrosio, Emanuele Pontali, Alessandro Wasum Mariani, Elisabetta Zampogna, Martin van den Boom, Antonio Spanevello and Giovanni Battista Migliori

Appl. Sci. 2020, 10(8), 2734; https://doi.org/10.3390/app10082734 - 15 Apr 2020

Cited by 10 | Viewed by 5393

Abstract

Even though the majority of tuberculosis (TB) programmes consider their work completed when a patient is ‘successfully’ cured, patients often continue to suffer with post-treatment or surgical sequelae. This review focuses on describing the available evidence with regard to the diagnosis and management [...] Read more.

Even though the majority of tuberculosis (TB) programmes consider their work completed when a patient is ‘successfully’ cured, patients often continue to suffer with post-treatment or surgical sequelae. This review focuses on describing the available evidence with regard to the diagnosis and management of post-treatment and surgical sequelae (pulmonary rehabilitation). We carried out a non-systematic literature review based on a PubMed search using specific key-words, including various combinations of ‘TB’, ‘MDR-TB’, ‘XDR-TB’, ‘surgery’, ‘functional evaluation’, ‘sequelae’ and ‘pulmonary rehabilitation’. References of the most important papers were retrieved to improve the search accuracy. We identified the main areas of interest to describe the topic as follows: 1) ‘Surgery’, described through observational studies and reviews, systematic reviews and meta-analyses, IPD (individual data meta-analyses), and official guidelines (GRADE (Grading of Recommendations Assessment, Development and Evaluation) or not GRADE-based); 2) Post-TB treatment functional evaluation; and 3) Pulmonary rehabilitation interventions. We also highlighted the priority areas for research for the three main areas of interest. The collection of high-quality standardized variables would allow advances in the understanding of the need for, and effectiveness of, pulmonary rehabilitation at both the individual and the programmatic level. The initial evidence supports the importance of the adequate functional evaluation of these patients, which is necessary to identify those who will benefit from pulmonary rehabilitation. Full article

(This article belongs to the Special Issue Tuberculosis Drug Discovery and Development 2019)

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18 pages, 692 KiB

Open AccessFeature PaperReview

Host-Directed Therapies and Anti-Virulence Compounds to Address Anti-Microbial Resistant Tuberculosis Infection

by Raphael Gries, Claudia Sala and Jan Rybniker

Appl. Sci. 2020, 10(8), 2688; https://doi.org/10.3390/app10082688 - 13 Apr 2020

Cited by 7 | Viewed by 4039

Abstract

Despite global efforts to contain tuberculosis (TB), the disease remains a leading cause of morbidity and mortality worldwide, further exacerbated by the increased resistance to antibiotics displayed by the tubercle bacillus Mycobacterium tuberculosis. In order to treat drug-resistant TB, alternative or complementary [...] Read more.

Despite global efforts to contain tuberculosis (TB), the disease remains a leading cause of morbidity and mortality worldwide, further exacerbated by the increased resistance to antibiotics displayed by the tubercle bacillus Mycobacterium tuberculosis. In order to treat drug-resistant TB, alternative or complementary approaches to standard anti-TB regimens are being explored. An area of active research is represented by host-directed therapies which aim to modulate the host immune response by mitigating inflammation and by promoting the antimicrobial activity of immune cells. Additionally, compounds that reduce the virulence of M. tuberculosis, for instance by targeting the major virulence factor ESX-1, are being given increased attention by the TB research community. This review article summarizes the current state of the art in the development of these emerging therapies against TB. Full article

(This article belongs to the Special Issue Tuberculosis Drug Discovery and Development 2019)

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15 pages, 1479 KiB

Open AccessFeature PaperReview

Update on TB Vaccine Pipeline

by Carlos Martin, Nacho Aguilo, Dessislava Marinova and Jesus Gonzalo-Asensio

Appl. Sci. 2020, 10(7), 2632; https://doi.org/10.3390/app10072632 - 10 Apr 2020

Cited by 33 | Viewed by 9828

Abstract

In addition to antibiotics, vaccination is considered among the most efficacious methods in the control and the potential eradication of infectious diseases. New safe and effective vaccines against tuberculosis (TB) could be a very important tool and are called to play a significant [...] Read more.

In addition to antibiotics, vaccination is considered among the most efficacious methods in the control and the potential eradication of infectious diseases. New safe and effective vaccines against tuberculosis (TB) could be a very important tool and are called to play a significant role in the fight against TB resistant to antimicrobials. Despite the extended use of the current TB vaccine Bacillus Calmette-Guérin (BCG), TB continues to be transmitted actively and continues to be one of the 10 most important causes of death in the world. In the last 20 years, different TB vaccines have entered clinical trials. In this paper, we review the current use of BCG and the diversity of vaccines in clinical trials and their possible indications. New TB vaccines capable of protecting against respiratory forms of the disease caused by sensitive or resistant Mycobacterium tuberculosis strains would be extremely useful tools helping to prevent the emergence of multi-drug resistance. Full article

(This article belongs to the Special Issue Tuberculosis Drug Discovery and Development 2019)

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20 pages, 619 KiB

Open AccessReview

Model-Informed Drug Discovery and Development Strategy for the Rapid Development of Anti-Tuberculosis Drug Combinations

by Rob C. van Wijk, Rami Ayoun Alsoud, Hans Lennernäs and Ulrika S. H. Simonsson

Appl. Sci. 2020, 10(7), 2376; https://doi.org/10.3390/app10072376 - 31 Mar 2020

Cited by 13 | Viewed by 7248

Abstract

The increasing emergence of drug-resistant tuberculosis requires new effective and safe drug regimens. However, drug discovery and development are challenging, lengthy and costly. The framework of model-informed drug discovery and development (MID3) is proposed to be applied throughout the preclinical to clinical phases [...] Read more.

The increasing emergence of drug-resistant tuberculosis requires new effective and safe drug regimens. However, drug discovery and development are challenging, lengthy and costly. The framework of model-informed drug discovery and development (MID3) is proposed to be applied throughout the preclinical to clinical phases to provide an informative prediction of drug exposure and efficacy in humans in order to select novel anti-tuberculosis drug combinations. The MID3 includes pharmacokinetic-pharmacodynamic and quantitative systems pharmacology models, machine learning and artificial intelligence, which integrates all the available knowledge related to disease and the compounds. A translational in vitro-in vivo link throughout modeling and simulation is crucial to optimize the selection of regimens with the highest probability of receiving approval from regulatory authorities. In vitro-in vivo correlation (IVIVC) and physiologically-based pharmacokinetic modeling provide powerful tools to predict pharmacokinetic drug-drug interactions based on preclinical information. Mechanistic or semi-mechanistic pharmacokinetic-pharmacodynamic models have been successfully applied to predict the clinical exposure-response profile for anti-tuberculosis drugs using preclinical data. Potential pharmacodynamic drug-drug interactions can be predicted from in vitro data through IVIVC and pharmacokinetic-pharmacodynamic modeling accounting for translational factors. It is essential for academic and industrial drug developers to collaborate across disciplines to realize the huge potential of MID3. Full article

(This article belongs to the Special Issue Tuberculosis Drug Discovery and Development 2019)

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33 pages, 15885 KiB

Open AccessReview

Oxidative Phosphorylation—an Update on a New, Essential Target Space for Drug Discovery in Mycobacterium tuberculosis

by Caroline Shi-Yan Foo, Kevin Pethe and Andréanne Lupien

Appl. Sci. 2020, 10(7), 2339; https://doi.org/10.3390/app10072339 - 29 Mar 2020

Cited by 28 | Viewed by 6998

Abstract

New drugs with new mechanisms of action are urgently required to tackle the global tuberculosis epidemic. Following the FDA-approval of the ATP synthase inhibitor bedaquiline (Sirturo^®), energy metabolism has become the subject of intense focus as a novel pathway to exploit [...] Read more.

New drugs with new mechanisms of action are urgently required to tackle the global tuberculosis epidemic. Following the FDA-approval of the ATP synthase inhibitor bedaquiline (Sirturo^®), energy metabolism has become the subject of intense focus as a novel pathway to exploit for tuberculosis drug development. This enthusiasm stems from the fact that oxidative phosphorylation (OxPhos) and the maintenance of the transmembrane electrochemical gradient are essential for the viability of replicating and non-replicating Mycobacterium tuberculosis (M. tb), the etiological agent of human tuberculosis (TB). Therefore, new drugs targeting this pathway have the potential to shorten TB treatment, which is one of the major goals of TB drug discovery. This review summarises the latest and key findings regarding the OxPhos pathway in M. tb and provides an overview of the inhibitors targeting various components. We also discuss the potential of new regimens containing these inhibitors, the flexibility of this pathway and, consequently, the complexity in targeting it. Lastly, we discuss opportunities and future directions of this drug target space. Full article

(This article belongs to the Special Issue Tuberculosis Drug Discovery and Development 2019)

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35 pages, 3474 KiB

Open AccessFeature PaperReview

Mycobacterial Cell Wall: A Source of Successful Targets for Old and New Drugs

by Catherine Vilchèze

Appl. Sci. 2020, 10(7), 2278; https://doi.org/10.3390/app10072278 - 27 Mar 2020

Cited by 40 | Viewed by 15742

Abstract

Eighty years after the introduction of the first antituberculosis (TB) drug, the treatment of drug-susceptible TB remains very cumbersome, requiring the use of four drugs (isoniazid, rifampicin, ethambutol and pyrazinamide) for two months followed by four months on isoniazid and rifampicin. Two of [...] Read more.

Eighty years after the introduction of the first antituberculosis (TB) drug, the treatment of drug-susceptible TB remains very cumbersome, requiring the use of four drugs (isoniazid, rifampicin, ethambutol and pyrazinamide) for two months followed by four months on isoniazid and rifampicin. Two of the drugs used in this “short”-course, six-month chemotherapy, isoniazid and ethambutol, target the mycobacterial cell wall. Disruption of the cell wall structure can enhance the entry of other TB drugs, resulting in a more potent chemotherapy. More importantly, inhibition of cell wall components can lead to mycobacterial cell death. The complexity of the mycobacterial cell wall offers numerous opportunities to develop drugs to eradicate Mycobacterium tuberculosis, the causative agent of TB. In the past 20 years, researchers from industrial and academic laboratories have tested new molecules to find the best candidates that will change the face of TB treatment: drugs that will shorten TB treatment and be efficacious against active and latent, as well as drug-resistant TB. Two of these new TB drugs block components of the mycobacterial cell wall and have reached phase 3 clinical trial. This article reviews TB drugs targeting the mycobacterial cell wall in use clinically and those in clinical development. Full article

(This article belongs to the Special Issue Tuberculosis Drug Discovery and Development 2019)

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11 pages, 974 KiB

Open AccessFeature PaperReview

Development of Macozinone for TB treatment: An Update

by Vadim Makarov and Katarína Mikušová

Appl. Sci. 2020, 10(7), 2269; https://doi.org/10.3390/app10072269 - 26 Mar 2020

Cited by 37 | Viewed by 4827

Abstract

Macozinone, a piperazine-benzothiazinone PBTZ169, is currently undergoing Phase 1/2 clinical studies for the treatment of tuberculosis (TB). In this review we summarize the key findings that led to the development of this compound and to identification of its target, decaprenylphospohoryl ribose oxidase DprE1, [...] Read more.

Macozinone, a piperazine-benzothiazinone PBTZ169, is currently undergoing Phase 1/2 clinical studies for the treatment of tuberculosis (TB). In this review we summarize the key findings that led to the development of this compound and to identification of its target, decaprenylphospohoryl ribose oxidase DprE1, which is involved in the synthesis of the essential arabinan polymers of the cell wall in a TB pathogen, Mycobacterium tuberculosis. We present the results of the pilot clinical studies, which raise optimism regarding its further development towards more efficient TB drug regimens. Full article

(This article belongs to the Special Issue Tuberculosis Drug Discovery and Development 2019)

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11 pages, 3161 KiB

Open AccessFeature PaperReview

Development of Delpazolid for the Treatment of Tuberculosis

by Young Lag Cho and Jichan Jang

Appl. Sci. 2020, 10(7), 2211; https://doi.org/10.3390/app10072211 - 25 Mar 2020

Cited by 25 | Viewed by 4287

Abstract

A novel oxazolidinone with cyclic amidrazone, delpazolid (LCB01-0371), was synthesized by LegoChem BioSciences, Inc. (Daejeon, Korea). Delpazolid can improve the minimum bactericidal concentration of Mycobacterium tuberculosis H37Rv and significantly reduce resistance rates, especially of multi-drug-resistant tuberculosis (MDR-TB) isolates, compared with linezolid. Therefore, delpazolid [...] Read more.

A novel oxazolidinone with cyclic amidrazone, delpazolid (LCB01-0371), was synthesized by LegoChem BioSciences, Inc. (Daejeon, Korea). Delpazolid can improve the minimum bactericidal concentration of Mycobacterium tuberculosis H37Rv and significantly reduce resistance rates, especially of multi-drug-resistant tuberculosis (MDR-TB) isolates, compared with linezolid. Therefore, delpazolid can be used to treat MDR-TB. The safety, tolerability, and pharmacokinetics of delpazolid have been evaluated in a phase 1 clinical trial, which revealed that it does not cause adverse events such as myelosuppression even after three weeks of repeated dosing. Interim efficacy and safety results, particularly those from a clinical phase 2a early bactericidal activity trial including patients with drug-susceptible tuberculosis, were reported and the findings will be further analyzed to guide phase 2a studies. Full article

(This article belongs to the Special Issue Tuberculosis Drug Discovery and Development 2019)

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17 pages, 280 KiB

Open AccessFeature PaperReview

Drug-Resistant Tuberculosis 2020: Where We Stand

by Angelo Iacobino, Lanfranco Fattorini and Federico Giannoni

Appl. Sci. 2020, 10(6), 2153; https://doi.org/10.3390/app10062153 - 22 Mar 2020

Cited by 46 | Viewed by 8193

Abstract

The control of tuberculosis (TB) is hampered by the emergence of multidrug-resistant (MDR) Mycobacterium tuberculosis (Mtb) strains, defined as resistant to at least isoniazid and rifampin, the two bactericidal drugs essential for the treatment of the disease. Due to the worldwide estimate of [...] Read more.

The control of tuberculosis (TB) is hampered by the emergence of multidrug-resistant (MDR) Mycobacterium tuberculosis (Mtb) strains, defined as resistant to at least isoniazid and rifampin, the two bactericidal drugs essential for the treatment of the disease. Due to the worldwide estimate of almost half a million incident cases of MDR/rifampin-resistant TB, it is important to continuously update the knowledge on the mechanisms involved in the development of this phenomenon. Clinical, biological and microbiological reasons account for the generation of resistance, including: (i) nonadherence of patients to their therapy, and/or errors of physicians in therapy management, (ii) complexity and poor vascularization of granulomatous lesions, which obstruct drug distribution to some sites, resulting in resistance development, (iii) intrinsic drug resistance of tubercle bacilli, (iv) formation of non-replicating, drug-tolerant bacilli inside the granulomas, (v) development of mutations in Mtb genes, which are the most important molecular mechanisms of resistance. This review provides a comprehensive overview of these issues, and releases up-dated information on the therapeutic strategies recently endorsed and recommended by the World Health Organization to facilitate the clinical and microbiological management of drug-resistant TB at the global level, with attention also to the most recent diagnostic methods. Full article

(This article belongs to the Special Issue Tuberculosis Drug Discovery and Development 2019)

19 pages, 4647 KiB

Open AccessFeature PaperReview

Promiscuous Targets for Antitubercular Drug Discovery: The Paradigm of DprE1 and MmpL3

by Giulia Degiacomi, Juan Manuel Belardinelli, Maria Rosalia Pasca, Edda De Rossi, Giovanna Riccardi and Laurent Roberto Chiarelli

Appl. Sci. 2020, 10(2), 623; https://doi.org/10.3390/app10020623 - 15 Jan 2020

Cited by 41 | Viewed by 5410

Abstract

The development and spread of Mycobacterium tuberculosis multi-drug resistant strains still represent a great global health threat, leading to an urgent need for novel anti-tuberculosis drugs. Indeed, in the last years, several efforts have been made in this direction, through a number of [...] Read more.

The development and spread of Mycobacterium tuberculosis multi-drug resistant strains still represent a great global health threat, leading to an urgent need for novel anti-tuberculosis drugs. Indeed, in the last years, several efforts have been made in this direction, through a number of high-throughput screenings campaigns, which allowed for the identification of numerous hit compounds and novel targets. Interestingly, several independent screening assays identified the same proteins as the target of different compounds, and for this reason, they were named “promiscuous” targets. These proteins include DprE1, MmpL3, QcrB and Psk13, and are involved in the key pathway for M. tuberculosis survival, thus they should represent an Achilles’ heel which could be exploited for the development of novel effective drugs. Indeed, among the last molecules which entered clinical trials, four inhibit a promiscuous target. Within this review, the two most promising promiscuous targets, the oxidoreductase DprE1 involved in arabinogalactan synthesis and the mycolic acid transporter MmpL3 are discussed, along with the latest advancements in the development of novel inhibitors with anti-tubercular activity. Full article

(This article belongs to the Special Issue Tuberculosis Drug Discovery and Development 2019)

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5 pages, 198 KiB

Open AccessFeature PaperCommentary

TB Elimination Requires Discovery and Development of Transformational Agents

by Christian Lienhardt and Mario C. Raviglione

Appl. Sci. 2020, 10(7), 2605; https://doi.org/10.3390/app10072605 - 10 Apr 2020

Cited by 5 | Viewed by 1612

Abstract

The World Health Organization (WHO) End Tuberculosis (TB) Strategy has set ambitious targets to reduce 2015 TB incidence and deaths by 80% and 90%, respectively, by the year 2030. Given the current rate of TB incidence decline (about 2% per year annually), reaching [...] Read more.

The World Health Organization (WHO) End Tuberculosis (TB) Strategy has set ambitious targets to reduce 2015 TB incidence and deaths by 80% and 90%, respectively, by the year 2030. Given the current rate of TB incidence decline (about 2% per year annually), reaching these targets will require new transformational tools and innovative ways to deliver them. In addition to improved tests for early and rapid detection of TB and universal drug-susceptibility testing, as well as novel vaccines for improved prevention, better, safer, shorter and more efficacious treatments for all forms of TB are needed. Only a handful of new drugs are currently in phase II or III clinical trials, and a few combination regimens are being tested, mainly for drug-resistant TB. In this article, capitalising on an increasingly rich medicine pipeline and taking advantage of new methodological designs with great potential, the main areas where progress is needed for a transformational improvement of treatment of all forms of TB are described. Full article

(This article belongs to the Special Issue Tuberculosis Drug Discovery and Development 2019)

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