Dataset Information

Cyclipostins and Cyclophostin analogs impair growth of Mycobacterium abscessus by inhibiting enzymes involved in many physiological processes

ABSTRACT: Mycobacterium abscessus is nowadays under the spotlight of the scientific community. This pathogenic mycobacteria is indeed responsible for a wide spectrum of infections involving mostly pulmonary infections in patients with cystic fibrosis. M. abscessus is intrinsically resistant to a broad range of antibiotics, including most antitubercular drugs, and is considered the most pathogenic and chemotherapy-resistant rapidly growing mycobacterium. Consequently, with very limited treatment options, the development of new therapeutic approaches to fight this pathogen are urgently needed. 38 new analogs of Cyclipostins & Cyclophostin (CyC), compounds naturally produced by Streptomyces species, have been synthesized. Their antibacterial activities against clinical isolates belonging to the M. chelonae-abscessus clade, as well as Gram-negative and Gram-positive bacteria have been evaluated by the REMA method. The intracellular activities of the CyC against intramacrophagic M. abscessus have also been investigated and compared to those of imipenem. The CyCs displayed very low toxicity towards host cells and their inhibitory activity was exclusively restricted to mycobacteria. The best candidate, CyC17, showed a high selectivity for mycobacteria with MIC values (<2 up to 40 µg/mL) comparable to those of most classical antibiotics used to treat M. abscessus infections. Of importance, several CyCs were active against extracellular M. abscessus growth (i.e., CyC17 / CyC18β / CyC25 / CyC26) or against intracellular mycobacteria inside macrophages (i.e., CyC7α,β / CyC8α,β) with MIC values similar to or better than those of standard antibiotics. Based on these results, we intended to identify the potential target enzymes of CyC17/CyC26 in M. abscessus by activity-based protein profiling (ABPP) approach coupled with mass spectrometry differential analysis.

INSTRUMENT(S): Orbitrap Fusion Lumos, LTQ Orbitrap Velos

ORGANISM(S): Mycobacterium Abscessus (strain Atcc 19977 / Dsm 44196 / Cip 104536 / Jcm 13569 / Nctc 13031 / Tmc 1543)

SUBMITTER: Luc Camoin

LAB HEAD: Luc Camoin

PROVIDER: PXD014255 | Pride | 2019-10-08

REPOSITORIES: Pride

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Publications

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

Madani Abdeldjalil A Ridenour Jeremy N JN Martin Benjamin P BP Paudel Rishi R RR Abdul Basir Anosha A Le Moigne Vincent V Herrmann Jean-Louis JL Audebert Stéphane S Camoin Luc L Kremer Laurent L Spilling Christopher D CD Canaan Stéphane S Cavalier Jean-François JF

ACS infectious diseases 20190725 9

Twelve new Cyclophostin and Cyclipostins analogues (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 toward host cells and were only active against myc ...[more]

PMID: 31299146

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Project description:The experiment was carried out during two vegetation seasons from 25th of April to 10th of September. Two Polish potato cultivars, the drought-tolerant Gwiazda and drought-sensitive Oberon were used. Selected tubers with transverse diameters of 3 - 4 cm were pre-sprouted for 2 weeks before planting. Plants were grown in a vegetation hall in pots filled with a thin layer of gravel on the bottom and the universal vegetable soil substrate ‘Hollas’ (Agaris Polska Ltd., Poland) produced from peat with the addition of chalk at a pH range of 5.5-6.5. Additionally, in phase 20 of the BBCH-scale of plant development, MIS-3 (Intermag) fertilizer was applied. Water content (WC) in volumetric basis in soil pots was measured according Black (1965). Weather conditions during the years of study were monitored using a Weather Campbell Station (Campbell Scientific Inc.) located in close proximity, and a thermohygrograph placed between pots. Meteorological data of air temperature, the photosynthetically active radiation, and humidity were comparable in the years of study and favorable for potato development. Three weeks after the initiation of the tuberisation phase (56 DAP), plants were divided into 3 groups, each consisting of 6 plants. The first group of plants was subjected to soil drought (remained without irrigation, day/night temperature 22°C/18°C), the second one to high temperature (day/night temperature 38°C/25°C) and the third one was watered according to needs and at optimal temperature (control plants, day/night temperature 22°C/18°C). Stress application lasted 14 days and finished at 70 DAP. During this period, plants were placed in phytotron equipped with six Hortilux Schreder Lamps with Philips light bulbs of 1600 W each. Air humidity was in the range 65-70%. WC under 14 days of soil drought reached 30% (v/v), and remained 80% (v/v) in control and high temperature conditions. During the recovery period, after 14 days of stress treatment, WC reached control levels. Plant root material for proteomic research was collected on the 14th day of stress treatment (70 DAP).

Project description:Echinoderm microtubule (MT)-associated protein-like 1 (Eml1) is mutated in the HeCo mouse, which exhibits subcortical band heterotopia (SBH), a developmental malformation of the cerebral cortex. EML1 mutations are also found in human patients affected by severe ribbon-like heterotopia, associated with epilepsy and intellectual disability (1). Neural progenitors in the ventricular zone (VZ) of the developing cerebral cortex undergo precisely regulated divisions, and mitotic perturbations contribute to pathological mechanisms (2). Eml1 is expressed in the mouse VZ and ectopic progenitors are present in the mutant developing cortex, when Eml1 is absent, at early stages of development (1). Thus, Eml1 is likely to play a role in neural progenitors during cortical development. We performed cell and molecular biology assays aiming to elucidate the function of Eml1 in neural progenitors, and explored the VZ of the HeCo mutant in order to find morphological perturbations that might explain the initiation of SBH formation (3). As part of this study, we searched for Eml1 molecular partners by pull-downs from mouse cortical extracts at embryonic day E13.5 and mass spectrometry (MS) analyses in order to identify the molecular pathways in which the protein is involved (3). Eml1 is formed by an N-terminal region that contains a dimerization domain and a C-terminal region that forms a ‘tandem atypical propeller in EMLs’ (TAPE) domain. The isolated N-terminal domain strongly binds MTs, while the C-terminal domain preferentially binds tubulin, and its beta-propeller structure is thought also to mediate the interaction with other molecules (4,5). We focused for this study on the N-terminal part of the protein (amino acids 1-178). Future study will validate or elucidate new interactions by using the C-terminal domain and/or the full-length protein. The results obtained from the N terminal MS data, integrated with other experimental findings, allow us to insert Eml1 in a network of proteins that are likely to regulate the assembly and function of the mitotic spindle in neural progenitors (3). More precisely, we showed that the protein regulates MT dynamics and its loss leads to perturbations in metaphase spindle length, which in turn impact progenitor morphology and behavior (3). References 1. Kielar, M., et al. Mutations in Eml1 lead to ectopic progenitors and neuronal heterotopia in mouse and human. Nat. Neurosci. 17, 923–933 (2014). 2. Bizzotto, S., & Francis, F. Morphological and functional aspects of progenitors perturbed in cortical malformations. Front Cell Neurosci. 9, 30; 10.3389/fncel00030 (2015). 3. Bizzotto, S., et al. Eml1 loss impairs apical progenitor spindle length and soma shape in the developing cerebral cortex. 4. Richards, M. W., et al. Crystal structure of EML1 reveals the basis for Hsp90 dependence of oncogenic EML4-ALK by disruption of an atypical β-propeller domain. Proc. Natl. Acad. Sci. U.S.A. 111, 5195–5200 (2014). 5. Richards, M. W., et al. Microtubule association of EML proteins and the EML4-ALK variant 3 oncoprotein require an N-terminal trimerization domain. Biochem. J. 467, 529–536 (2015).

Dataset Information

Cyclipostins and Cyclophostin analogs impair growth of Mycobacterium abscessus by inhibiting enzymes involved in many physiological processes

Publications

Cyclipostins and Cyclophostin Analogues as Multitarget Inhibitors That Impair Growth of <i>Mycobacterium abscessus</i>.

Similar Datasets

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