Altered drug efflux under iron deprivation unveils abrogated MmpL3 driven mycolic acid transport and fluidity in mycobacteria

Pal, Rahul; Hameed, Saif; Fatima, Zeeshan

doi:10.1007/s10534-018-0157-8

Cited by 15 publications

(12 citation statements)

References 51 publications

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“…S1). These results are consistent with biochemical analysis of Fe-deprived mycobacterial cells that showed reduction of surface mycolates and enhanced cell envelope permeability (16, 17). Additionally, we found the ultrastructural changes observed in the virR mutant correlated with increased susceptibility to the muramidase lysozyme and increased release of muropeptides relative to WT (Fig.…”

Section: Resultssupporting

confidence: 89%

“…Our ultrastructural analysis of hypervesiculating Mtb cells suggested a close link between EV release and cell envelope alterations. Our microscopy observations that indicate loss of OM thickness in Fe-limited Mtb are consistent with previous analysis of the cell envelope of Fe deficient Mtb which showed reduced cell envelope lipids (16) and enhanced cell envelope permeability (16, 36) associated with downregulation of mmpL3 (17). MmmpL3 transports trehalose monomycolate across the plasma membrane for outer membrane assembly (37).…”

Section: Discussionsupporting

confidence: 91%

“…MmmpL3 transports trehalose monomycolate across the plasma membrane for outer membrane assembly (37). Our transcriptomic analysis showed additional genes required for MA and glycolipid biosynthesis that are repressed in Fe-limited Mtb (Fig S1) (16, 17). Modification of cell envelope lipids during Fe-limitation may directly influence EV release by increasing cell envelope permeability and through induction of iniBAC .…”

Section: Discussionmentioning

confidence: 96%

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Dynamin-like proteins are essential for vesicle biogenesis inMycobacterium tuberculosis

Gupta

Palacios

Khataokar

et al. 2020

Preprint

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30 31 Mycobacterium tuberculosis (Mtb) secretes pathogenicity factors and immunologically active 32 molecules via membrane vesicles. However, nothing is known about the mechanisms involved 33 in mycobacterial vesicle biogenesis. This study investigates molecular determinants of 34 membrane vesicle production in Mtb by analyzing Mtb cells under conditions of high vesicle 35 production: iron limitation and VirR restriction. Ultrastructural analysis showed extensive cell 36 envelope restructuring in association with vesicle release that correlated with downregulation 37 of cell surface lipid biosynthesis and peptidoglycan alterations. Comparative transcriptomics 38 showed common upregulation of the iniBAC operon in association with high vesicle production 39 in Mtb cells. Vesicle production analysis demonstrated that the dynamin-like proteins (DLPs) 40 encoded by this operon, IniA and IniC, are necessary for release of EV by Mtb in culture and in 41 infected macrophages. Isoniazid, a first-line antibiotic, used in tuberculosis treatment, was 42 found to stimulate vesicle release in a DLP-dependent manner. Our results provide a new 43 understanding of the function of mycobacterial DLPs and mechanistic insights into vesicle 44 biogenesis. The findings will enable further understanding of the relevance of Mtb-derived 45 extracellular vesicles in the pathogenesis of tuberculosis and may open new avenues for 46 therapeutic research. 47 48 49 3 IMPORTANCE 50 Iron is an essential nutrient that promotes survival and growth of M. tuberculosis, the bacterium 51 that causes human tuberculosis (TB). Limited availability of iron, often encountered in the host 52 environment, stimulates M. tuberculosis to secrete membrane-bound extracellular vesicles 53 containing molecules that may help it evade the immune system. Characterizing the bacterial 54 factors and mechanisms involved in the production of mycobacterial vesicles is important for 55 envisioning ways to interfere with this process. Here, we report the discovery of proteins 56 required by M. tuberculosis for vesicle biogenesis in culture and during host cell infection. We 57 also demonstrate a connection between antibiotic response and extracellular vesicle 58 production. The work provides insights into the mechanisms underlying vesicle biogenesis in 59 M. tuberculosis and permits better understanding of the significance of vesicle production to M. 60 tuberculosis-host interactions and antibiotic stress response. 61 62 63 4 64 65 Extracellular vesicles (EV) are membrane-bound structures actively secreted by most, if not all, 66 cells and play important roles in intercellular communication. Bacteria release EV containing 67 proteins, genetic material, and lipids to communicate with both prokaryotic and eukaryotic cells 68 in their environment (1, 2).69 M. tuberculosis (Mtb), the causative agent of human tuberculosis (TB), releases EV during 70 axenic growth and into the macrophages it infects, both in culture and in the lungs of infected 71 mice (3). Mtb-produced EV (Mtb-EV)...

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Section: Resultssupporting

confidence: 89%

Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 96%

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Dynamin-like proteins are essential for vesicle biogenesis inMycobacterium tuberculosis

Gupta

Palacios

Khataokar

et al. 2020

Preprint

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“…Interestingly, several psychotropic drugs, including the antipsychotic loxapine, phenothiazines, and selective serotonin reuptake inhibitors (SSRIs) were found to effectively block microbial DEPs, probably explaining their selective bactericidal action against Bacteroidetes phylum ( 126 – 128 ). Moreover, iron chelators were recently found to be effective DEP-inhibitors, a property that may explain their bactericidal action against the iron-dependent Bacteroides phylum ( 129 ). Indeed, another reason, Bacteroidetes phylum may be more susceptible to psychotropic drugs is that, unlike Firmicutes and Actinobacteria that can synthesize heme, Bacteroidetes, which lack the enzymatic machinery to synthesize this iron protein, depend on scavenging it from the colonic environment ( 82 , 130 , 131 ).…”

Section: Psychotropic Drugs As Antimicrobialsmentioning

confidence: 99%

The Other Obesity Epidemic—Of Drugs and Bugs

et al. 2020

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Chronic psychiatric patients with schizophrenia and related disorders are frequently treatment-resistant and may require higher doses of psychotropic drugs to remain stable. Prolonged exposure to these agents increases the risk of weight gain and cardiometabolic disorders, leading to poorer outcomes and higher medical cost. It is well-established that obesity has reached epidemic proportions throughout the world, however it is less known that its rates are two to three times higher in mentally ill patients compared to the general population. Psychotropic drugs have emerged as a major cause of weight gain, pointing to an urgent need for novel interventions to attenuate this unintended consequence. Recently, the gut microbial community has been linked to psychotropic drugs-induced obesity as these agents were found to possess antimicrobial properties and trigger intestinal dysbiosis, depleting Bacteroidetes phylum. Since germ-free animals exposed to psychotropics have not demonstrated weight gain, altered commensal flora composition is believed to be necessary and sufficient to induce dysmetabolism. Conversely, not only do psychotropics disrupt the composition of gut microbiota but the later alter the metabolism of the former. Here we review the role of gut bacterial community in psychotropic drugs metabolism and dysbiosis. We discuss potential biomarkers reflecting the status of Bacteroidetes phylum and take a closer look at nutritional interventions, fecal microbiota transplantation, and transcranial magnetic stimulation, strategies that may lower obesity rates in chronic psychiatric patients.

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“…Rv0203 was identified as extracellular protein that binds heme with a K d of 5.4 × 10 −6 M. It has a unique structural fold and is proposed to function as a substrate binding protein, grabbing heme in the extracellular space and guiding the molecule to MmpL3/11 for subsequent uptake (Owens et al, 2013(Owens et al, , 2012. Recently, Pal et al (2018) reported abrogated MmpL3 driven mycolic acid transport under iron ion deprivation providing a first link between the dual assigned roles of MmpL3 as metal importer and lipid exporter. Recent studies of Mitra et al (2017Mitra et al ( , 2019 implied that a second set of proteins (Ppe36, Ppe62, FecB2, and DppA) is potentially involved in heme import mechanisms in mycobacteria.…”

Section: Introductionmentioning

confidence: 99%

The Two-Component Locus MSMEG_0244/0246 Together With MSMEG_0243 Affects Biofilm Assembly in M. smegmatis Correlating With Changes in Phosphatidylinositol Mannosides Acylation

Gašparovič

Weng

et al. 2020

Front. Microbiol.

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Ferric and ferrous iron is an essential transition metal for growth of many bacterial species including mycobacteria. The genomic region msmeg_0234 to msmeg_0252 from Mycobacterium smegmatis is putatively involved in iron/heme metabolism. We investigate the genes encoding the presumed two component system MSMEG_0244/MSMEG_0246, the neighboring gene msmeg_0243 and their involvement in this process. We show that purified MSMEG_0243 indeed is a heme binding protein. Deletion of msmeg_0243/msmeg_0244/msmeg_0246 in Mycobacterium smegmatis leads to a defect in biofilm formation and colony growth on solid agar, however, this phenotype is independent of the supplied iron source. Further, analysis of the corresponding mutant and its lipids reveals that changes in morphology and biofilm formation correlate with altered acylation patterns of phosphatidylinositol mannosides (PIMs). We provide the first evidence that msmeg_0244/msmeg_0246 work in concert in cellular lipid homeostasis, especially in the maintenance of PIMs, with the heme-binding protein MSMEG_0243 as potential partner.

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Altered drug efflux under iron deprivation unveils abrogated MmpL3 driven mycolic acid transport and fluidity in mycobacteria

Cited by 15 publications

References 51 publications

Dynamin-like proteins are essential for vesicle biogenesis inMycobacterium tuberculosis

Dynamin-like proteins are essential for vesicle biogenesis inMycobacterium tuberculosis

The Other Obesity Epidemic—Of Drugs and Bugs

The Two-Component Locus MSMEG_0244/0246 Together With MSMEG_0243 Affects Biofilm Assembly in M. smegmatis Correlating With Changes in Phosphatidylinositol Mannosides Acylation

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