Oxadiazolone derivatives, new promising multi-target inhibitors against M. tuberculosis

Nguyen, Phuong Chi; Delorme, Vincent; Bénarouche, Anaïs; Guy, Alexandre; Landry, Valérie; Audebert, Stéphane; Pophillat, Matthieu; Camoin, Luc; Crauste, Céline; Galano, Jean‐Marie; Durand, Thierry; Brodin, Priscille; Canaan, Stéphane; Cavalier, Jean‐François

doi:10.1016/j.bioorg.2018.08.025

Cited by 20 publications

(68 citation statements)

References 67 publications

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“…leading to bacterial growth inhibition were first determined using the resazurin microtiter assay (REMA). 7,10,55 Briefly, log-phase bacteria were diluted to a cell density of 5 × 10 6 cells/mL and 100 µL of this inoculum was grown in a 96-well plate in the presence of serial dilutions of compounds.…”

Section: Resazurin Microtiter Assay (Rema) For Mic Determination Thementioning

confidence: 99%

Cyclipostins and Cyclophostin Analogues as Multitarget Inhibitors That Impair Growth of Mycobacterium abscessus

et al. 2019

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Twelve new Cyclophostin and Cyclipostins analogs (CyC19-30) were synthesized, thus extending our series to 38 CyCs. Their antibacterial activities were evaluated against four pathogenic mycobacteria (Mycobacterium abscessus, Mycobacterium marinum, Mycobacterium bovis BCG and Mycobacterium tuberculosis) and two Gram negative bacteria. The CyCs displayed very low toxicity towards host cells and were only active against mycobacteria. Importantly, several CyCs were active against extracellular M. abscessus (CyC17/CyC18β/CyC25/CyC26) or intramacrophage residing mycobacteria (CyC7(α,β)/CyC8(α,β)) with minimal inhibitory concentrations (MIC50) values comparable to or better than those of amikacin or imipenem, respectively. An activity-based protein profiling combined with mass spectrometry allowed identification of the potential target enzymes of CyC17/CyC26, mostly being involved in lipid metabolism and/or in cell wall biosynthesis. Overall, these results strengthen the selective activity of the CyCs against mycobacteria, including the most drug-resistant M. abscessus, through the cumulative inhibition of a large number of Ser-and Cysenzymes participating in key physiological processes.

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Section: Resazurin Microtiter Assay (Rema) For Mic Determination Thementioning

confidence: 99%

Cyclipostins and Cyclophostin Analogues as Multitarget Inhibitors That Impair Growth of Mycobacterium abscessus

et al. 2019

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“…Finally, in view of testing our compounds in future ex vivo experiments, their toxicity against murine Raw264.7 macrophages was further investigated using a classical dose–response assay . The calculated response parameter was CC 50 , which corresponds to the concentration required to elicit a 50 % decrease in cell viability. Except for compounds VM003 and VM006, no cytotoxicity against Raw264.7 macrophages was observed at the highest concentration tested (125 μg mL −1 ), yielding a selectivity index (SI=CC 50 /MIC 50 ) for VM008 in the range of >6.3 to >22.3 for M. tb and M. marinum , respectively (Table ).…”

Section: Resultsmentioning

confidence: 99%

“…Relative fluorescence units were defined as: RFU (%)=[(test well FU)/(mean FU of B wells)]×100. MIC values were determined by fitting the % RFU sigmoidal dose–response curves in KaleidaGraph 4.2 software (Synergy Software) as previously reported . The lowest drug concentration required to inhibit 50 % of bacterial growth was defined as the MIC 50 value.…”

Section: Methodsmentioning

confidence: 99%

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Synthesis of Long‐Chain β‐Lactones and Their Antibacterial Activities against Pathogenic Mycobacteria

et al. 2019

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In the quest for new antibacterial agents, a series of novel long‐ and medium‐chain mono‐ and disubstituted β‐lactones was developed. Their activity against three pathogenic mycobacteria—M. abscessus, M. marinum, and M. tuberculosis—was assessed by the resazurin microtiter assay (REMA). Among the 16 β‐lactones synthesized, only 3‐hexadecyloxetan‐2‐one (VM005) exhibited promising activity against M. abscessus, whereas most of the β‐lactones showed interesting activities against M. marinum, similar to that of the classical antibiotic, isoniazid. Regarding M. tuberculosis, six compounds were found to be active against this mycobacterium, with β‐lactone VM008 [trans‐(Z)‐3‐(hexadec‐7‐en‐1‐yl)‐4‐propyloxetan‐2‐one] being the best growth inhibitor. The promising antibacterial activities of the best compounds in this series suggest that these molecules may serve as leads for the development of much more efficient antimycobacterial agents.

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“…Due to the worldwide increasing incidence and prevalence of M. abscessus and the inherent difficulties to manage such resistant pulmonary infections, new active molecules are urgently needed. In this context, we recently investigated the antibacterial activities of 19 oxadiazolonecore (OX) derivatives (Fig 1) against three pathogenic slow-growing mycobacteria: M. marinum, M. bovis BCG as well as M. tuberculosis H37Rv the etiologic agent of tuberculosis [12].…”

Section: Introductionmentioning

confidence: 99%

Dissecting the antibacterial activity of oxadiazolone-core derivatives against Mycobacterium abscessus

et al. 2020

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Mycobacterium abscessus (M. abscessus), a rapidly growing mycobacterium, is an emergent opportunistic pathogen responsible for chronic bronchopulmonary infections in individuals with respiratory diseases such as cystic fibrosis. Most treatments of M. abscessus pulmonary infections are poorly effective due to the intrinsic resistance of this bacteria against a broad range of antibiotics including anti-tuberculosis agents. Consequently, the number of drugs that are efficient against M. abscessus remains limited. In this context, 19 oxadiazolone (OX) derivatives have been investigated for their antibacterial activity against both the rough (R) and smooth (S) variants of M. abscessus. Several OXs impair extracellular M. abscessus growth with moderated minimal inhibitory concentrations (MIC), or act intracellularly by inhibiting M. abscessus growth inside infected macrophages with MIC values similar to those of imipenem. Such promising results prompted us to identify the potential target enzymes of the sole extra and intracellular inhibitor of M. abscessus growth, i.e., compound iBpPPOX, via activity-based protein profiling combined with mass spectrometry. This approach led to the identification of 21 potential protein candidates being mostly involved in M. abscessus lipid metabolism and/or in cell wall biosynthesis. Among them, the Ag85C protein has been confirmed as a vulnerable target of iBpPPOX. This study clearly emphasizes the potential of the OX derivatives to inhibit the extracellular and/or intracellular growth of M. abscessus by targeting various enzymes potentially involved in many physiological processes of this most drug-resistant mycobacterial species.

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Oxadiazolone derivatives, new promising multi-target inhibitors against M. tuberculosis

Cited by 20 publications

References 67 publications

Cyclipostins and Cyclophostin Analogues as Multitarget Inhibitors That Impair Growth of Mycobacterium abscessus

Cyclipostins and Cyclophostin Analogues as Multitarget Inhibitors That Impair Growth of Mycobacterium abscessus

Synthesis of Long‐Chain β‐Lactones and Their Antibacterial Activities against Pathogenic Mycobacteria

Dissecting the antibacterial activity of oxadiazolone-core derivatives against Mycobacterium abscessus

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