Mechanism of Action, Resistance, Synergism, and Clinical Implications of Delamanid Against Multidrug-Resistant Mycobacterium tuberculosis

Khoshnood, Saeed; Taki, Elahe; Sadeghifard, Nourkhoda; Kaviar, Vahab Hassan; Haddadi, Mohammad Hossein; Farshadzadeh, Zahra; Kouhsari, Ebrahim; Goudarzi, Mehdi; Heidary, Mohsen

doi:10.3389/fmicb.2021.717045

Cited by 37 publications

(21 citation statements)

References 95 publications

(137 reference statements)

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“…Andreas H. Diacon (12) also found that the CFU of smear-positive pulmonary tuberculosis patients decreased rapidly after treatment with Dlm for 2 days. It was suggested that Dlm may accumulate in the cell and has potential activity against the intra-and extracellular bacilli (13). Thirdly, the bactericidal activity of Dlm was concentrationdependent.…”

Section: Discussionmentioning

confidence: 99%

The Activities and Secretion of Cytokines Caused by Delamanid on Macrophages Infected by Multidrug-Resistant Mycobacterium tuberculosis Strains

et al. 2021

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BackgroundDelamanid (Dlm) is an effective drug against drug-susceptible and drug-resistant Mycobacterium tuberculosis strains, including Multidrug-resistant Mycobacterium tuberculosis (MDR-MTB). There are few reports on the activity and secretion of cytokines caused by Dlm on macrophages infected by MDR-MTB strains. Therefore, this article aims to observe the bactericidal activity and secretion of cytokines of the macrophages infected by MDR-MTB strains after Dlm was administered, so as to provide a basis for further perfecting the mechanism of Dlm.MethodsSamples were respectively collected to count the intracellular colony-forming unit (CFU) of macrophages infected by MDR-MTB or H37Rv strains at 4, 8, 24, and 48 h after Dlm at MIC, 10MIC, and 20MIC were administered. Samples were respectively collected to detect the level of IL-12/23 p40, TNF-α, IL-6, and IL-10 in the culture supernatant of macrophages infected by MDR-MTB or H37Rv strains at 4, 24, and 48 h after Dlm at MIC were administered. The levels of four cytokines in the culture supernatant were measured using the Luminex® 200™ (Luminex, USA) according to the manufacturer’s instructions. Data were analyzed by SPSS 25.0 software. The continuous data in normal distribution were expressed as mean ± standard deviation (x¯ ± s) and analyzed by t or F test. P<0.05 was considered statistically significant.Results(1) After Dlm was applied to macrophages infected by MDR-MTB strains:(A) The intracellular CFU gradually decreased, reached the lowest value at 48 h, and was lower than that of Dlm before administration and infection group (P<0.05). (B) The intracellular CFU was further reduced after increasing Dlm dose to 10MIC and 20MIC, and the latter was lower than that of the former (P<0.05). (C) The intracellular CFU of MDR-MTB group was higher than that of H37Rv group at 4~48 h after administration (P<0.05). (2) After Dlm at MIC dose was applied to macrophages infected by MDR-MTB strains: (A) The level of IL-12/23 p40 at any time didn’t change compared with that of Dlm before administration (P>0.05), while the level of IL-12/23 p40 at 4 h was higher than that of the infection group (P<0.05). The levels of TNF-α at 24 and 48 h were higher than that of Dlm before administration (P<0.05), but were similar to that of the infection group (P>0.05). In addition, the levels of IL-12/23 p40 and TNF-α at any time were similar to that of the H37Rv group after administration (P>0.05). (B) The levels of IL-6 at 24 and 48 h were higher than that of Dlm before administration (P<0.05), but were similar to that of H37Rv group (P>0.05) and were lower than that of infection group (P<0.05). The level of IL-10 at any time didn’t change compared with that of Dlm before administration (P>0.05), but was lower than that of the infection group at 4~48 h and was lower than that of the H37Rv group at 24 h (P<0.05). (C) The level of IL-12/23 p40 and IL-10 didn’t change with the change of intracellular CFU (P<0.05), while the level of TNF-α and IL-6 increased with the intracellular CFU decreasing, and the increase level of TNF-α was lower than that of the infection group (P<0.05).ConclusionsDlm had strong bactericidal activity against intracellular MDR-MTB, which was time-dependent and concentration-dependent. Its bactericidal activity against intracellular MDR-MTB strains was weaker than that against drug-susceptible tuberculosis strains. Dlm might have immunomodulatory effect, inducing low expression of Th2 cytokines IL-6 and IL-10 at different times after administration.

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Section: Discussionmentioning

confidence: 99%

The Activities and Secretion of Cytokines Caused by Delamanid on Macrophages Infected by Multidrug-Resistant Mycobacterium tuberculosis Strains

et al. 2021

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“…It also inhibits bacterial respiration. [27,28] F I G U R E 2 Delamanid and TBA-354 are the modified versions of pretomanid…”

Section: Pretomanid (Pa-824)mentioning

confidence: 99%

“…The obtained compounds were evaluated for their anti-TB activity out of which three compounds (25-27) (Figure 13) were chosen as the hit compounds, each with an MIC value of 1 μg/ml in the first screening and MIC of 0.625 μg/ml in the second screening against mycobacterial H 37 Rv strain. [125] There was a significant increase in activity of the hit moieties due to the substitution of the substituent groups (Me [25], 4-trifluoromethylphenyl [26], and dimethylamino [27]). Docking of receptor enoyl-ACP reductase was used to identify the mode of action of the active compounds 25-27.…”

Section: Fluoroquinolone Is a Promising Subunit In Treating Tbmentioning

confidence: 99%

Drug re‐engineering and repurposing: A significant and rapid approach to tuberculosis drug discovery

Reddy

Sinha

Kumar

et al. 2022

Archiv der Pharmazie

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The prevalence of tuberculosis (TB) remains the leading cause of death from a single infectious agent, ranking it above all other contagious diseases. The problem to tackle this disease seems to become even worse due to the outbreak of SARS-CoV-2.Further, the complications related to drug-resistant TB, prolonged treatment regimens, and synergy between TB and HIV are significant drawbacks. There are several drugs to treat TB, but there is still no rapid and accurate treatment available.Intensive research is, therefore, necessary to discover newer molecular analogs that can probably eliminate this disease within a short span. An increase in efficacy can be achieved through re-engineering old TB-drug families and repurposing known drugs.These two approaches have led to the production of newer classes of compounds with novel mechanisms to treat multidrug-resistant strains. With respect to this context, we discuss structural aspects of developing new anti-TB drugs as well as examine advances in TB drug discovery. It was found that the fluoroquinolone, oxazolidinone, and nitroimidazole classes of compounds have greater potential to be further explored for TB drug development. Most of the TB drug candidates in the clinical phase are modified versions of these classes of compounds. Therefore, here we anticipate that modification or repurposing of these classes of compounds has a higher probability to reach the clinical phase of drug development. The information provided will pave the way for researchers to design and identify newer molecular analogs for TB drug development and also broaden the scope of exploring future-generation potent, yet safer anti-TB drugs.

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“…Delamanid (12) is recognized as an inhibitor of mycolic acid synthesis [19] and is thought to undergo the same activation process and exhibit the same mechanism of action as pretomanid (6).…”

Section: Tuberculosismentioning

confidence: 99%

“…Fungal endophyte PSU-N24 was isolated from the branch of Garcinia nigrolineata collected in Thailand, and was fermented to produce 9α-hydroxyhalorosellinia A (18), which was found to have an MIC of 13.3 µg/mL after testing against M. tuberculosis H37Ra [26]. Desoxybostrycin (19) and 9β-hydroxydihydrodesoxybostrycin (20) produced by the same fungus were found to be less active against M. tuberculosis H37Ra, having an MIC of 50 and 25 µg/mL, respectively [26]. Diaporthe sp.…”

Section: Compounds From Endophytic Fungi and Plant-pathogenic Fungimentioning

confidence: 99%

Fungal-derived compounds and mycogenic nanoparticles with antimycobacterial activity: a review

et al. 2022

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Tuberculosis (TB) is a persistent lung infection caused by Mycobacterium tuberculosis. The disease is characterized by high mortality rates of over 1 million per year. Unfortunately, the potency and effectiveness of currently used anti-TB drugs is gradually decreasing due to the constant development of persistence and resistance by M. tuberculosis. The adverse side effects associated with current anti-TB drugs, along with anti-TB drug resistance, present an opportunity to bio-prospect novel potent anti-TB drugs from unique sources. Fundamentally, fungi are a rich source of bioactive secondary metabolites with valuable therapeutic potential. Enhancing the potency and effectiveness of fungal-based anti-TB drug leads by chemical synthesis and/or modification with nanomaterials, may result in the discovery of novel anti-TB drugs. In this review, the antimycobacterial activity of fungal-derived compounds and mycogenic nanoparticles are summarized. Numerous fungal-derived compounds as well as some mycogenic nanoparticles that exhibit strong antimycobacterial activity that is comparable to that of approved drugs, were found. If fully explored, fungi holds the promise to become key drivers in the generation of lead compounds in TB-drug discovery initiatives.

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Mechanism of Action, Resistance, Synergism, and Clinical Implications of Delamanid Against Multidrug-Resistant Mycobacterium tuberculosis

Cited by 37 publications

References 95 publications

The Activities and Secretion of Cytokines Caused by Delamanid on Macrophages Infected by Multidrug-Resistant Mycobacterium tuberculosis Strains

The Activities and Secretion of Cytokines Caused by Delamanid on Macrophages Infected by Multidrug-Resistant Mycobacterium tuberculosis Strains

Drug re‐engineering and repurposing: A significant and rapid approach to tuberculosis drug discovery

Fungal-derived compounds and mycogenic nanoparticles with antimycobacterial activity: a review

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