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Molecules
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Antitubercular Drug Discovery: Implication and Challenges
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Antitubercular Drug Discovery: Implication and Challenges

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

Deadline for manuscript submissions: closed (30 June 2023) | Viewed by 16537

Special Issue Editors

Dr. Jonathan Sellars

E-Mail Website
Guest Editor
Faculty of Medical Sciences, Newcastle University, Newcastle-upon-Tyne NE1 7RU, UK
Interests: antibacterials; organic chemistry; antibiotic resistance; Mycobacterium tuberculosis; proteomics; drug discovery; assays
Special Issues, Collections and Topics in MDPI journals
Dr. Alistair Brown

E-Mail Website
Guest Editor
The Faculty of Medical Sciences, Biosciences Institute, Cookson Building, Newcastle University, Newcastle-upon-Tyne NE2 4HH, UK
Interests: antibacterials; antibiotic resistance; Mycobacterium tuberculosis; drug discovery; assays; lipid biochemistry; lipid degradation; mycobacterial physiology

Special Issue Information

Dear Colleagues,

Tuberculosis (TB) is a communicable disease which is responsible for long-term illness and continues to be one of the top ten causes of death worldwide from a single infectious agent. In 2018, an estimated ten million (range 9.0–11.1 million) new cases of TB infection were reported, equivalent to 132 cases per 100,000. Unfortunately, treatment responses against TB are stagnating, and most WHO regions are now likely to fail to reach the 2020 milestone of the WHO’s End TB strategy. Concerningly, there is an ever-increasing number of infections from strains which are resistant to frontline anti-TB drugs, further exacerbating the global TB epidemic.

Consequently, the challenges presented by these issues must be faced head on, and therefore, this Special Issue aims to bring together innovative research from the development of new drug molecules with novel modes of action to the microbiological, and clinical research underpinning the disease complexities will be considered for inclusion.

Dr. Jonathan Sellars
Dr. Alistair Brown
Guest Editors

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
  • actinomycetes
  • antitubercular
  • mechanism of resistance
  • drug discovery
  • antibiotic resistance
  • systems biology
  • drug development

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Published Papers (5 papers)

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Research

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20 pages, 10744 KiB  
Article
Conformational Dynamics and Stability of Bilayers Formed by Mycolic Acids from the Mycobacterium tuberculosis Outer Membrane
by Liana A. Savintseva, Ilya S. Steshin, Alexander A. Avdoshin, Sergey V. Panteleev, Alexey V. Rozhkov, Ekaterina A. Shirokova, Grigory D. Livshits, Alexander V. Vasyankin, Eugene V. Radchenko, Stanislav K. Ignatov and Vladimir A. Palyulin
Molecules 2023, 28(3), 1347; https://doi.org/10.3390/molecules28031347 - 31 Jan 2023
Cited by 7 | Viewed by 2079
Abstract
Bilayers of mycolic acids (MAs) form the outer membrane of Mycobacterium tuberculosis that has high strength and extremely low permeability for external molecules (including antibiotics). For the first time, we were able to study them using the all-atom long-term molecular dynamic simulations (from [...] Read more.
Bilayers of mycolic acids (MAs) form the outer membrane of Mycobacterium tuberculosis that has high strength and extremely low permeability for external molecules (including antibiotics). For the first time, we were able to study them using the all-atom long-term molecular dynamic simulations (from 300 ns up to 1.2 μs) in order to investigate the conformational changes and most favorable structures of the mycobacterial membranes. The structure and properties of the membranes are crucially dependent on the initial packing of the α-mycolic acid (AMA) molecules, as well as on the presence of the secondary membrane components, keto- and methoxy mycolic acids (KMAs and MMAs). In the case of AMA-based membranes, the most labile conformation is W while other types of conformations (sU as well as sZ, eU, and eZ) are much more stable. In the multicomponent membranes, the presence of the KMA and MMA components (in the W conformation) additionally stabilizes both the W and eU conformations of AMA. The membrane in which AMA prevails in the eU conformation is much thicker and, at the same time, much denser. Such a packing of the MA molecules promotes the formation of a significantly stronger outer mycobacterial membrane that should be much more resistant to the threatening external factors. Full article
(This article belongs to the Special Issue Antitubercular Drug Discovery: Implication and Challenges)
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14 pages, 1373 KiB  
Article
Riminophenazine Derivatives as Potential Antituberculosis Agents: Synthesis, Biological, and Electrochemical Evaluations
by Mpelegeng Victoria Bvumbi, Chris van der Westhuyzen, Edwin M. Mmutlane and Andile Ngwane
Molecules 2021, 26(14), 4200; https://doi.org/10.3390/molecules26144200 - 10 Jul 2021
Cited by 3 | Viewed by 2514
Abstract
A series of novel riminophenazine derivatives, having ionizable alkyl substituents at N-5 and a variety of substituents on the C-3 imino nitrogen, at C-8 and on the pendant aryl group, have been designed and synthesized. Preliminary investigations into the relationship between lipophilicity, redox [...] Read more.
A series of novel riminophenazine derivatives, having ionizable alkyl substituents at N-5 and a variety of substituents on the C-3 imino nitrogen, at C-8 and on the pendant aryl group, have been designed and synthesized. Preliminary investigations into the relationship between lipophilicity, redox potential, and antimycobacterial activity were conducted, using the in vitro activity against Mycobacterium tuberculosis H37Rv, mammalian cytotoxicity, and the redox potential of the compounds determined by cyclic voltammetry as measures. Results revealed an activity “cliff” associated with C-8 substitution (10l and 10m) that, along with defined redox activity, point to a new class of riminophenazines as potential anti-tuberculosis agents having reasonable activity (MIC99 ~1 µM). Full article
(This article belongs to the Special Issue Antitubercular Drug Discovery: Implication and Challenges)
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Review

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26 pages, 10657 KiB  
Review
Tools to Alleviate the Drug Resistance in Mycobacterium tuberculosis
by Ali A. Rabaan, Abbas Al Mutair, Hawra Albayat, Jawaher Alotaibi, Tarek Sulaiman, Mohammed Aljeldah, Basim R. Al Shammari, Amal H. Alfaraj, Mona A. Al Fares, Sara Alwarthan, Abdulwahab Z. Binjomah, Mohammed S. Alzahrani, Hatem M. Alhani, Mohammed S. Almogbel, Abdulmonem A. Abuzaid, Ghaya Alqurainees, Fatimah Al Ibrahim, Ali H. Alhaddad, Mubarak Alfaresi, Nadira Al-baghli and Saad Alhumaidadd Show full author list remove Hide full author list
Molecules 2022, 27(20), 6985; https://doi.org/10.3390/molecules27206985 - 17 Oct 2022
Cited by 2 | Viewed by 4376
Abstract
Mycobacterium tuberculosis (Mtb), an acid-fast bacillus that causes Tuberculosis (TB), is a pathogen that caused 1.5 million deaths in 2020. As per WHO estimates, another 4.1 million people are suffering from latent TB, either asymptomatic or not diagnosed, and the frequency [...] Read more.
Mycobacterium tuberculosis (Mtb), an acid-fast bacillus that causes Tuberculosis (TB), is a pathogen that caused 1.5 million deaths in 2020. As per WHO estimates, another 4.1 million people are suffering from latent TB, either asymptomatic or not diagnosed, and the frequency of drug resistance is increasing due to intrinsically linked factors from both host and bacterium. For instance, poor access to TB diagnosis and reduced treatment in the era of the COVID-19 pandemic has resulted in more TB deaths and an 18% reduction in newly diagnosed cases of TB. Additionally, the detection of Mtb isolates exhibiting resistance to multiple drugs (MDR, XDR, and TDR) has complicated the scenario in the pathogen’s favour. Moreover, the conventional methods to detect drug resistance may miss mutations, making it challenging to decide on the treatment regimen. However, owing to collaborative initiatives, the last two decades have witnessed several advancements in both the detection methods and drug discovery against drug-resistant isolates. The majority of them belong to nucleic acid detection techniques. In this review, we highlight and summarize the molecular mechanism underlying drug resistance in Mtb, the recent advancements in resistance detection methods, and the newer drugs used against drug-resistant TB. Full article
(This article belongs to the Special Issue Antitubercular Drug Discovery: Implication and Challenges)
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15 pages, 835 KiB  
Review
Promising Antimycobacterial Activities of Flavonoids against Mycobacterium sp. Drug Targets: A Comprehensive Review
by Ali A. Rabaan, Saad Alhumaid, Hawra Albayat, Mohammed Alsaeed, Fadwa S. Alofi, Mawaheb H. Al-Howaidi, Safaa A. Turkistani, Salah M. Alhajri, Hejji E. Alahmed, Abdulwahab B. Alzahrani, Mutaib M. Mashraqi, Sara Alwarthan, Mashael Alhajri, Fatimah S. Alshahrani, Souad A. Almuthree, Roua A. Alsubki, Abdulmonem A. Abuzaid, Mubarak Alfaresi, Mona A. Al Fares and Abbas Al Mutair
Molecules 2022, 27(16), 5335; https://doi.org/10.3390/molecules27165335 - 22 Aug 2022
Cited by 13 | Viewed by 3560
Abstract
Tuberculosis (TB) caused by the bacterial pathogen Mycobacterium tuberculosis (Mtb) remains a threat to mankind, with over a billion of deaths in the last two centuries. Recent advancements in science have contributed to an understanding of Mtb pathogenesis and developed effective [...] Read more.
Tuberculosis (TB) caused by the bacterial pathogen Mycobacterium tuberculosis (Mtb) remains a threat to mankind, with over a billion of deaths in the last two centuries. Recent advancements in science have contributed to an understanding of Mtb pathogenesis and developed effective control tools, including effective drugs to control the global pandemic. However, the emergence of drug resistant Mtb strains has seriously affected the TB eradication program around the world. There is, therefore, an urgent need to develop new drugs for TB treatment, which has grown researchers’ interest in small molecule-based drug designing and development. The small molecules-based treatments hold significant potential to overcome drug resistance and even provide opportunities for multimodal therapy. In this context, various natural and synthetic flavonoids were reported for the effective treatment of TB. In this review, we have summarized the recent advancement in the understanding of Mtb pathogenesis and the importance of both natural and synthetic flavonoids against Mtb infection studied using in vitro and in silico methods. We have also included flavonoids that are able to inhibit the growth of non-tubercular mycobacterial organisms. Hence, understanding the therapeutic properties of flavonoids can be useful for the future treatment of TB. Full article
(This article belongs to the Special Issue Antitubercular Drug Discovery: Implication and Challenges)
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23 pages, 10913 KiB  
Review
Quinoxaline Moiety: A Potential Scaffold against Mycobacterium tuberculosis
by Marc Montana, Vincent Montero, Omar Khoumeri and Patrice Vanelle
Molecules 2021, 26(16), 4742; https://doi.org/10.3390/molecules26164742 - 5 Aug 2021
Cited by 28 | Viewed by 2874
Abstract
Background. The past decades have seen numerous efforts to develop new antitubercular agents. Currently, the available regimens are lengthy, only partially effective, and associated with high rates of adverse events. The challenge is therefore to develop new agents with faster and more [...] Read more.
Background. The past decades have seen numerous efforts to develop new antitubercular agents. Currently, the available regimens are lengthy, only partially effective, and associated with high rates of adverse events. The challenge is therefore to develop new agents with faster and more efficient action. The versatile quinoxaline ring possesses a broad spectrum of pharmacological activities, ensuring considerable attention to it in the field of medicinal chemistry. Objectives. In continuation of our program on the pharmacological activity of quinoxaline derivatives, this review focuses on potential antimycobacterial activity of recent quinoxaline derivatives and discusses their structure—activity relationship for designing new analogs with improved activity. Methods. The review compiles recent studies published between January 2011 and April 2021. Results. The final total of 23 studies were examined. Conclusions. Data from studies of quinoxaline and quinoxaline 1,4-di-N-oxide derivatives highlight that specific derivatives show encouraging perspectives in the treatment of Mycobacterium tuberculosis and the recent growing interest for these scaffolds. These interesting results warrant further investigation, which may allow identification of novel antitubercular candidates based on this scaffold. Full article
(This article belongs to the Special Issue Antitubercular Drug Discovery: Implication and Challenges)
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