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Recent Advances in Antitubercular Drug Discovery

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (31 December 2019) | Viewed by 23643

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Special Issue Editor

Dr. Chiarelli Laurent

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Guest Editor

Department of Biology and Biotechnology “Lazzaro Spallanzani”, University of Pavia, 27100 Pavia, Italy
Interests: antitubercular; Mycobacterium tuberculosis; Mycobacterium abscessus; drug resistance
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Tuberculosis (TB) is still the leading cause of death from a single infectious disease agent, with an estimated 1.7 billion people infected with Mycobacterium tuberculosis, and more than 10 million new cases each year. The current anti-TB therapy has reduced the mortality, but it requires a long treatment period, and can have serious adverse reactions. Moreover, multidrug-resistant (MDR) and extensively drug-resistant (XDR) M. tuberculosis strains have now spread worldwide and become a global issue. For these reasons novel TB drugs and novel drug targets are needed; indeed, considerable efforts, involving different approaches and expertise, have been made in the last years.

The aim of this Special Issue is, therefore, to collect research papers, short communications, and critical review articles, that are focused on the discovery and development of novel antitubercular drugs, new potential biological targets, and therapeutic approaches.

Dr. Laurent Chiarelli
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Tuberculosis
M. tuberculosis
Resistance mechanisms
Small molecules
Natural products
Drug design
Computational tools
Structure–activity relationships

Published Papers (4 papers)

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Research

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17 pages, 1466 KiB

Open AccessArticle

Identification and Repurposing of Trisubstituted Harmine Derivatives as Novel Inhibitors of Mycobacterium tuberculosis Phosphoserine Phosphatase

by Elise Pierson, Marie Haufroid, Tannu Priya Gosain, Pankaj Chopra, Ramandeep Singh and Johan Wouters

Molecules 2020, 25(2), 415; https://doi.org/10.3390/molecules25020415 - 19 Jan 2020

Cited by 10 | Viewed by 3367

Abstract

Mycobacterium tuberculosis is still the deadliest bacterial pathogen worldwide and the increasing number of multidrug-resistant tuberculosis cases further complicates this global health issue. M. tuberculosis phosphoserine phosphatase SerB2 is a promising target for drug design. Besides being a key essential metabolic enzyme of the pathogen’s serine pathway, it appears to be involved in immune evasion mechanisms. In this work, a malachite green-based phosphatase assay has been used to screen 122 compounds from an internal chemolibrary. Trisubstituted harmine derivatives were found among the best hits that inhibited SerB2 activity. Synthesis of an original compound helped to discuss a brief structure activity relationship evaluation. Kinetics experiments showed that the most potent derivatives inhibit the phosphatase in a parabolic competitive fashion with apparent inhibition constants (

K_{i}

) values in the micromolar range. Their interaction modes with the enzyme were investigated through induced fit docking experiments, leading to results consistent with the experimental data. Cellular assays showed that the selected compounds also inhibited M. tuberculosis growth in vitro. Those promising results may provide a basis for the development of new antimycobacterial agents targeting SerB2. Full article

(This article belongs to the Special Issue Recent Advances in Antitubercular Drug Discovery)

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Review

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36 pages, 4877 KiB

Open AccessReview

Mycobacterium tuberculosis Shikimate Pathway Enzymes as Targets for the Rational Design of Anti-Tuberculosis Drugs

by José E. S. Nunes, Mario A. Duque, Talita F. de Freitas, Luiza Galina, Luis F. S. M. Timmers, Cristiano V. Bizarro, Pablo Machado, Luiz A. Basso and Rodrigo G. Ducati

Molecules 2020, 25(6), 1259; https://doi.org/10.3390/molecules25061259 - 11 Mar 2020

Cited by 36 | Viewed by 11138

Abstract

Roughly a third of the world’s population is estimated to have latent Mycobacterium tuberculosis infection, being at risk of developing active tuberculosis (TB) during their lifetime. Given the inefficacy of prophylactic measures and the increase of drug-resistant M. tuberculosis strains, there is a clear and urgent need for the development of new and more efficient chemotherapeutic agents, with selective toxicity, to be implemented on patient treatment. The component enzymes of the shikimate pathway, which is essential in mycobacteria and absent in humans, stand as attractive and potential targets for the development of new drugs to treat TB. This review gives an update on published work on the enzymes of the shikimate pathway and some insight on what can be potentially explored towards selective drug development. Full article

(This article belongs to the Special Issue Recent Advances in Antitubercular Drug Discovery)

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17 pages, 3041 KiB

Open AccessReview

Multitargeting Compounds: A Promising Strategy to Overcome Multi-Drug Resistant Tuberculosis

by Giovanni Stelitano, José Camilla Sammartino and Laurent Roberto Chiarelli

Molecules 2020, 25(5), 1239; https://doi.org/10.3390/molecules25051239 - 09 Mar 2020

Cited by 20 | Viewed by 4357

Abstract

Tuberculosis is still an urgent global health problem, mainly due to the spread of multi-drug resistant M. tuberculosis strains, which lead to the need of new more efficient drugs. A strategy to overcome the problem of the resistance insurgence could be the polypharmacology approach, to develop single molecules that act on different targets. Polypharmacology could have features that make it an approach more effective than the classical polypharmacy, in which different drugs with high affinity for one target are taken together. Firstly, for a compound that has multiple targets, the probability of development of resistance should be considerably reduced. Moreover, such compounds should have higher efficacy, and could show synergic effects. Lastly, the use of a single molecule should be conceivably associated with a lower risk of side effects, and problems of drug–drug interaction. Indeed, the multitargeting approach for the development of novel antitubercular drugs have gained great interest in recent years. This review article aims to provide an overview of the most recent and promising multitargeting antitubercular drug candidates. Full article

(This article belongs to the Special Issue Recent Advances in Antitubercular Drug Discovery)

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15 pages, 1245 KiB

Open AccessFeature PaperReview

Targeting Genome Integrity in Mycobacterium Tuberculosis: From Nucleotide Synthesis to DNA Replication and Repair

by Riccardo Miggiano, Castrese Morrone, Franca Rossi and Menico Rizzi

Molecules 2020, 25(5), 1205; https://doi.org/10.3390/molecules25051205 - 07 Mar 2020

Cited by 12 | Viewed by 4284

Abstract

Mycobacterium tuberculosis (MTB) is the causative agent of tuberculosis (TB), an ancient disease which still today causes 1.4 million deaths worldwide per year. Long-term, multi-agent anti-tubercular regimens can lead to the anticipated non-compliance of the patient and increased drug toxicity, which in turn can contribute to the emergence of drug-resistant MTB strains that are not susceptible to first- and second-line available drugs. Hence, there is an urgent need for innovative antitubercular drugs and vaccines. A number of biochemical processes are required to maintain the correct homeostasis of DNA metabolism in all organisms. Here we focused on reviewing our current knowledge and understanding of biochemical and structural aspects of relevance for drug discovery, for some such processes in MTB, and particularly DNA synthesis, synthesis of its nucleotide precursors, and processes that guarantee DNA integrity and genome stability. Overall, the area of drug discovery in DNA metabolism appears very much alive, rich of investigations and promising with respect to new antitubercular drug candidates. However, the complexity of molecular events that occur in DNA metabolic processes requires an accurate characterization of mechanistic details in order to avoid major flaws, and therefore the failure, of drug discovery approaches targeting genome integrity. Full article

(This article belongs to the Special Issue Recent Advances in Antitubercular Drug Discovery)

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