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Molecules
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New Drugs against Tuberculosis and Mycobacterium abscessus Infections
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New Drugs against Tuberculosis and Mycobacterium abscessus Infections

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 8811

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

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Keywords

  • Mycobacterium tuberculosis
  • Mycobacterium abscessus
  • drug discovery
  • lead optimization
  • antibiotics

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Published Papers (3 papers)

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Research

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19 pages, 15182 KiB  
Article
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 2175
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) [...] Read more.
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)
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16 pages, 976 KiB  
Article
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
Cited by 1 | Viewed by 3208
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 [...] Read more.
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)
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Review

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13 pages, 1588 KiB  
Review
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 10 | Viewed by 2696
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. [...] Read more.
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)
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