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Dual-active oxadiazoles targeting the Mycobacterium tuberculosis ESX-1 secretion system and boosting ethionamide activity

ABSTRACT: Dual-active oxadiazoles targeting the Mycobacterium tuberculosis ESX-1 secretion system and boosting ethionamide activity

PROVIDER: PRJNA940393 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR23689518_1.fastq.gz	Fastqsanger.gz
	SRR23689518_2.fastq.gz	Fastqsanger.gz
	SRR23689519_1.fastq.gz	Fastqsanger.gz
	SRR23689519_2.fastq.gz	Fastqsanger.gz
	SRR23689520_1.fastq.gz	Fastqsanger.gz

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Dual-active oxadiazoles targeting the Mycobacterium tuberculosis ESX-1 secretion system and boosting ethionamide activity

Project description:To find potential regulatory targets of the anti-virulence compound S3 in Mycobacterium tubercuolsis.

2024-01-01 | GSE226474 | GEO

Transcription profiling of Mycobacterium bovis with pYUB412 and pRD1-2F9 genes knocked-in to investigate the ESX-1 secretion system

Project description:The dedicated secretion system ESX-1 of Mycobacterium tuberculosis encoded by the extended RD1 region (extRD1) assures export of the ESAT-6 protein and its partner, the 10 kDa culture filtrate protein CFP-10, and is missing from the vaccine strains M.bovis BCG and M.microti. Here, we systematically investigated the involvement of each individual ESX-1 gene in the secretion of both antigens, specific immunogenicity and virulence. ESX-1-complemented BCG and M.microti strains were more efficiently engulfed by bone marrow derived macrophages than controls and this may account for the enhanced in vivo growth of ESX-1 carrying strains. Inactivation of gene pe35 (Rv3872) impaired expression of CFP-10 and ESAT-6 suggesting a role in regulation. Genes Rv3868, Rv3869, Rv3870, Rv3871 and Rv3877 encoding an ATP-dependent chaperone and translocon were essential for secretion of ESAT-6 and CFP-10 in contrast to ppe68 (Rv3873) and Rv3876, whose inactivation did not impair secretion of ESAT-6. A strict correlation was found between ESAT-6 export and the generation of ESAT-6 specific T-cell responses in mice. Furthermore, ESAT-6 secretion and specific immunogenicity were almost always correlated with enhanced virulence in the SCID mouse model. Only loss of Rv3865 and part of Rv3866 did not affect ESAT-6 secretion or immunogenicity, but led to attenuation. This suggests that Rv3865/66 represent a new virulence factor that is independent from ESAT-6 secretion. This study has allowed us to identify new aspects of the extRD1 region of M.tuberculosis and to explore its role in the pathogenesis of tuberculosis. Data is also available from http://bugs.sgul.ac.uk/E-BUGS-31

2007-01-30 | E-BUGS-31 | biostudies-arrayexpress

WhiB6 is required for the secretion-dependent regulation of ESX-1 substrates in pathogenic mycobacteria

Project description:These data show that WhiB6 is required for the secretion-dependent regulation of ESX-1 substrates and ESX-1 substrates are regulated independently from the structural components, both during infection and as a result of active secretion.

2018-12-25 | GSE124341 | GEO

Proteolytic-independent role of mycosins in stabilization of the ESX-1 and ESX-5 type VII secretion membrane complexes.

Project description:Pathogenic mycobacteria contain up to five type VII secretion (T7S) systems, ESX-1 to ESX-5, which have central roles in virulence and viability. One of the conserved components of these systems, the serine protease mycosin (MycP), has been shown to be essential for secretion by ESX-1 and ESX-5. However, here we show that protease activity of MycP1 and MycP5 of M. marinum is not essential for ESX-1 and ESX-5 dependent secretion, respectively. This indicates that MycP has a second, so far unknown, function that is essential for T7S. To investigate whether this second role is related to proper functioning of the T7S membrane core complex, we first verified that the ESX-1 membrane complex is of similar composition and size as the previously analyzed ESX-5 complex and that MycP1 and MycP5 are not an integral part of the respective core complex. In contrast, we could not detect ESX-1 and ESX-5 complexes under mycP1 and mycP5 knockout conditions, respectively. Interestingly, the ESX-5 complex could be detected at wild-type levels in the absence of MycP5, when membranes were subjected to crosslinking before detergent solubilization, suggesting that MycP is involved in complex stabilization. Based on our findings we hypothesize that mycosins loosely associate with their respective membrane complex, which is crucial for the full integrity and functioning of the secretion machinery.

2016-10-11 | PXD003766 | Pride

The ESX-4 type VII secretion system in required for efficient heme utilization by Mycobacterium tuberculosis

Project description:In this study our primary objective was to identify unknown components that are required of Mtb Hm acquisition. Herein, we show that the ancestral ESX-4 type VII secretion system (T7SS) which was thought to be inactive in Mtb is required for efficient Hm utilization. We also identified that the culture filtrate proteins Rv0125 and Rv1085c and the alternative sigma factor SigM are necessary of Hm utilization. Finally, we present the first direct evidence that some mycobacterial PPE proteins are pore forming membrane proteins.

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2018-08-02 | PXD008905 | Pride

The loss of the PDIM/PGL virulence lipids causes differential secretion of ESX-1 sub-strates in Mycobacterium marinum

Project description:Raw and processed files in support of manuscript The loss of the PDIM/PGL virulence lipids causes differential secretion of ESX-1 sub-strates in Mycobacterium marinum The Virulence Lipid PDIM/PGL is essential for optimal protein secretion in Mycobacte-rium marinum WT, PDIM and complement strains lysate and culture filtrate analysis of proteomes

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WhiB6 is required for the secretion-dependent regulation of ESX-1 substrates in pathogenic mycobacteria

Project description:WhiB6 is required for the secretion-dependent regulation of ESX-1 substrates in pathogenic mycobacteria

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How Mycobacterium tuberculosis builds a home: Single-cell analysis reveals M. tuberculosis ESX-1-mediated accumulation of anti-inflammatory macrophages in infected mouse lungs

Project description:Mycobacterium tuberculosis (MTB) infects and replicates in lung mononuclear phagocytes (MNPs) with astounding ability to evade elimination. A virulence determinant that contributes to MTB’s ability to survive within MNPs is ESX-1, a type VII secretion system. However, how MTB virulence factors influence mononuclear cell recruitment and/or differentiation remains unknown. Here, using single-cell RNA sequencing, we studied the role of ESX-1 in MNP heterogenicity and response in mice and murine bone marrow-derived macrophages. We found that ESX-1 is required for MTB to recruit diverse MNP subsets with high MTB burden. Further, MTB induces an anti-inflammatory signature that may lead to more permissive MNPs. Spatial transcriptomics revealed an upregulation of anti-inflammatory signals in MTB lesions, where monocyte-derived macrophages concentrate near MTB-infected cells. Together, our findings suggest that MTB ESX-1 mediates the recruitment and differentiation of anti-inflammatory MNPs, which MTB can infect and manipulate for survival.

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How Mycobacterium tuberculosis builds a home: Single-cell analysis reveals M. tuberculosis ESX-1-mediated accumulation of anti-inflammatory macrophages in infected mouse lungs

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