Submit to Molecules Review for Molecules Propose a Special Issue

Journal Browser

► Journal Browser

New Drugs against Tuberculosis and Mycobacterium abscessus Infections

Print Special Issue Flyer
Special Issue Editors
Special Issue Information
Keywords
Published Papers

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

Deadline for manuscript submissions: closed (30 April 2023) | Viewed by 7009

Share This Special Issue

Special Issue Editors

Prof. Dr. Peter Imming

E-Mail Website
Guest Editor

Department of Pharmaceutical Chemistry, Martin-Luther-Universitaet Halle-Wittenberg, Halle, Germany
Interests: drug design; drug synthesis; antimycobacterial compounds; synthetic medicinal chemistry; near-infrared spectroscopy; drug quality control

Dr. Adrian Richter

E-Mail Website
Guest Editor

Department of Pharmaceutical Chemistry, Martin-Luther-Universitaet Halle-Wittenberg, Halle, Germany
Interests: medicinal chemistry; non-tuberculous mycobacteria; Mycobacterium abscessus; RNA polymerase; microbiology

Special Issue Information

Dear Colleagues,

Mycobacterial infections represent a major challenge for anti-infective therapy, and can often only be treated inadequately with approved antibiotics. There are hardly any effective drugs available for the treatment of resistant tuberculosis and for infections with non-tuberculous mycobacteria such as M. abscessus and M. avium. The establishment of new therapy concepts and drug classes is therefore of central importance in order to shorten the duration of therapy and to enable the treatment of infections with resistant pathogens. The interaction of new predictive in vitro assays, mode of action studies and the investigation of structure–activity relationships is necessary for this, and will be addressed in this Special Issue.

Prof. Dr. Peter Imming
Dr. Adrian Richter
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

Mycobacterium tuberculosis
Mycobacterium abscessus
drug discovery
lead optimization
antibiotics

Published Papers (3 papers)

Download All Papers

Research

Jump to: Review

19 pages, 15182 KiB

Open AccessArticle

Identification of Small Molecule Inhibitors against Mycobacteria in Activated Macrophages

by Rebecca Vande Voorde, Elizaveta Dzalamidze, Dylan Nelson and Lia Danelishvili

Molecules 2022, 27(18), 5824; https://doi.org/10.3390/molecules27185824 - 8 Sep 2022

Cited by 3 | Viewed by 1703

Abstract

Mycobacterial pathogens are intrinsically resistant to many available antibiotics, making treatment extremely challenging, especially in immunocompromised individuals and patients with underlying and chronic lung conditions. Even with lengthy therapy and the use of a combination of antibiotics, clinical success for non-tuberculous mycobacteria (NTM) is achieved in fewer than half of the cases. The need for novel antibiotics that are effective against NTM is urgent. To identify such new compounds, a whole cell high-throughput screen (HTS) was performed in this study. Compounds from the Chembridge DIVERSet library were tested for their ability to inhibit intracellular survival of M. avium subsp. hominissuis (MAH) expressing dtTomato protein, using fluorescence as a readout. Fifty-eight compounds were identified to significantly inhibit fluorescent readings of MAH. In subsequent assays, it was found that treatment of MAH-infected THP-1 macrophages with 27 of 58 hit compounds led to a significant reduction in intracellular viable bacteria, while 19 compounds decreased M. abscessus subsp. abscessus (Mab) survival rates within phagocytic cells. In addition, the hit compounds were tested in M. tuberculosis H37Ra (Mtb) and 14 compounds were found to exhibit activity in activated THP-1 cells. While the majority of compounds displayed inhibitory activity against both replicating (extracellular) and non-replicating (intracellular) forms of bacteria, a set of compounds appeared to be effective exclusively against intracellular bacteria. The efficacy of these compounds was examined in combination with current antibiotics and survival of both NTM and Mtb were evaluated within phagocytic cells. In time-kill dynamic studies, it was found that co-treatment promoted increased bacterial clearance when compared with the antibiotic or compound group alone. This study describes promising anti-NTM and anti-Mtb compounds with potential novel mechanisms of action that target intracellular bacteria in activated macrophages. Full article

(This article belongs to the Special Issue New Drugs against Tuberculosis and Mycobacterium abscessus Infections)

► Show Figures

Figure 1

16 pages, 976 KiB

Open AccessArticle

Hit Compounds and Associated Targets in Intracellular Mycobacterium tuberculosis

by Clement K. M. Tsui, Flavia Sorrentino, Gagandeep Narula, Alfonso Mendoza-Losana, Ruben Gonzalez del Rio, Esther Pérez Herrán, Abraham Lopez, Adama Bojang, Xingji Zheng, Modesto Jesus Remuiñán-Blanco and Yossef Av-Gay

Molecules 2022, 27(14), 4446; https://doi.org/10.3390/molecules27144446 - 12 Jul 2022

Viewed by 2466

Abstract

Mycobacterium tuberculosis (Mtb), the etiological agent of tuberculosis, is one of the most devastating infectious agents in the world. Chemical-genetic characterization through in vitro evolution combined with whole genome sequencing analysis was used identify novel drug targets and drug resistance genes in Mtb associated with its intracellular growth in human macrophages. We performed a genome analysis of 53 Mtb mutants resistant to 15 different hit compounds. We found nonsynonymous mutations/indels in 30 genes that may be associated with drug resistance acquisitions. Beyond confirming previously identified drug resistance mechanisms such as rpoB and lead targets reported in novel anti-tuberculosis drug screenings such as mmpL3, ethA, and mbtA, we have discovered several unrecognized candidate drug targets including prrB. The exploration of the Mtb chemical mutant genomes could help novel drug discovery and the structural biology of compounds and associated mechanisms of action relevant to tuberculosis treatment. Full article

(This article belongs to the Special Issue New Drugs against Tuberculosis and Mycobacterium abscessus Infections)

► Show Figures

Figure 1

Review

Jump to: Research

13 pages, 1588 KiB

Open AccessReview

Why Matter Matters: Fast-Tracking Mycobacterium abscessus Drug Discovery

by Uday S. Ganapathy and Thomas Dick

Molecules 2022, 27(20), 6948; https://doi.org/10.3390/molecules27206948 - 17 Oct 2022

Cited by 9 | Viewed by 2184

Abstract

Unlike Tuberculosis (TB), Mycobacterium abscessus lung disease is a highly drug-resistant bacterial infection with no reliable treatment options. De novo M. abscessus drug discovery is urgently needed but is hampered by the bacterium’s extreme drug resistance profile, leaving the current drug pipeline underpopulated. One proposed strategy to accelerate de novo M. abscessus drug discovery is to prioritize screening of advanced TB-active compounds for anti-M. abscessus activity. This approach would take advantage of the greater chance of homologous drug targets between mycobacterial species, increasing hit rates. Furthermore, the screening of compound series with established structure–activity-relationship, pharmacokinetic, and tolerability properties should fast-track the development of in vitro anti-M. abscessus hits into lead compounds with in vivo efficacy. In this review, we evaluated the effectiveness of this strategy by examining the literature. We found several examples where the screening of advanced TB chemical matter resulted in the identification of anti-M. abscessus compounds with in vivo proof-of-concept, effectively populating the M. abscessus drug pipeline with promising new candidates. These reports validate the screening of advanced TB chemical matter as an effective means of fast-tracking M. abscessus drug discovery. Full article

(This article belongs to the Special Issue New Drugs against Tuberculosis and Mycobacterium abscessus Infections)

► Show Figures