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Keywords = anti-TB drug pipeline

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36 pages, 8173 KiB  
Review
Amino Acid Biosynthesis Inhibitors in Tuberculosis Drug Discovery
by Michela Guida, Chiara Tammaro, Miriana Quaranta, Benedetta Salvucci, Mariangela Biava, Giovanna Poce and Sara Consalvi
Pharmaceutics 2024, 16(6), 725; https://doi.org/10.3390/pharmaceutics16060725 - 28 May 2024
Cited by 2 | Viewed by 2415
Abstract
According to the latest World Health Organization (WHO) report, an estimated 10.6 million people were diagnosed with tuberculosis (TB) in 2022, and 1.30 million died. A major concern is the emergence of multi-drug-resistant (MDR) and extensively drug-resistant (XDR) strains, fueled by the length [...] Read more.
According to the latest World Health Organization (WHO) report, an estimated 10.6 million people were diagnosed with tuberculosis (TB) in 2022, and 1.30 million died. A major concern is the emergence of multi-drug-resistant (MDR) and extensively drug-resistant (XDR) strains, fueled by the length of anti-TB treatment and HIV comorbidity. Innovative anti-TB agents acting with new modes of action are the only solution to counteract the spread of resistant infections. To escape starvation and survive inside macrophages, Mtb has evolved to become independent of the host by synthesizing its own amino acids. Therefore, targeting amino acid biosynthesis could subvert the ability of the mycobacterium to evade the host immune system, providing innovative avenues for drug discovery. The aim of this review is to give an overview of the most recent progress in the discovery of amino acid biosynthesis inhibitors. Among the hits discovered over the past five years, tryptophan (Trp) inhibitors stand out as the most advanced and have significantly contributed to demonstrating the feasibility of this approach for future TB drug discovery. Future efforts should be directed at prioritizing the chemical optimization of these hits to enrich the TB drug pipeline with high-quality leads. Full article
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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 14 | Viewed by 3197
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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17 pages, 486 KiB  
Review
Pre-Clinical Tools for Predicting Drug Efficacy in Treatment of Tuberculosis
by Hasmik Margaryan, Dimitrios D. Evangelopoulos, Leticia Muraro Wildner and Timothy D. McHugh
Microorganisms 2022, 10(3), 514; https://doi.org/10.3390/microorganisms10030514 - 26 Feb 2022
Cited by 4 | Viewed by 3171
Abstract
Combination therapy has, to some extent, been successful in limiting the emergence of drug-resistant tuberculosis. Drug combinations achieve this advantage by simultaneously acting on different targets and metabolic pathways. Additionally, drug combination therapies are shown to shorten the duration of therapy for tuberculosis. [...] Read more.
Combination therapy has, to some extent, been successful in limiting the emergence of drug-resistant tuberculosis. Drug combinations achieve this advantage by simultaneously acting on different targets and metabolic pathways. Additionally, drug combination therapies are shown to shorten the duration of therapy for tuberculosis. As new drugs are being developed, to overcome the challenge of finding new and effective drug combinations, systems biology commonly uses approaches that analyse mycobacterial cellular processes. These approaches identify the regulatory networks, metabolic pathways, and signaling programs associated with M. tuberculosis infection and survival. Different preclinical models that assess anti-tuberculosis drug activity are available, but the combination of models that is most predictive of clinical treatment efficacy remains unclear. In this structured literature review, we appraise the options to accelerate the TB drug development pipeline through the evaluation of preclinical testing assays of drug combinations. Full article
(This article belongs to the Special Issue Mycobacterial Infections: Diagnostics, Biomarkers and Treatment)
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19 pages, 2888 KiB  
Review
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 15 | Viewed by 5499
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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