The Role of Fur in the Transcriptional and Iron Homeostatic Response of Enterococcus faecalis

Latorre, Mauricio; Quenti, Daniela; Travisany, Dante; Singh, Kavindra V.; Murray, Barbara E.; Maass, Alejandro; Cambiazo, Verónica

doi:10.3389/fmicb.2018.01580

Cited by 26 publications

(54 citation statements)

References 63 publications

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“…ESKAPE pathogens share similar iron-mediated regulatory mechanisms of gene expression, all possessing the Ferric uptake regulator protein Fur, which drives the expression of iron-repressible genes, including those for siderophore-biosynthesis (i.e., basA ). Therefore, it can be assumed that the basA :: lacZ transcriptional fusion provides an indirect estimate of the intracellular iron levels of ESKAPE bacteria grown in different media (Ochsner and Vasil, 1996 ; Achenbach and Yang, 1997 ; Haley and Skaar, 2012 ; Mortensen and Skaar, 2013 ; Carpenter and Payne, 2014 ; Latorre et al, 2018 ). The ability of ESKAPE pathogens to grow in DMHB and RPMI-HS was then tested for the reference strains of each species (Figure S2 ).…”

Section: Resultsmentioning

confidence: 99%

Antimicrobial Activity of Gallium Compounds on ESKAPE Pathogens

Hijazi

Visaggio

Pirolo

et al. 2018

Front. Cell. Infect. Microbiol.

100

127

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ESKAPE bacteria are a major cause of multidrug-resistant infections, and new drugs are urgently needed to combat these pathogens. Given the importance of iron in bacterial physiology and pathogenicity, iron uptake and metabolism have become attractive targets for the development of new antibacterial drugs. In this scenario, the FDA-approved iron mimetic metal Gallium [Ga(III)] has been successfully repurposed as an antimicrobial drug. Ga(III) disrupts ferric iron-dependent metabolic pathways, thereby inhibiting microbial growth. This work provides the first comparative assessment of the antibacterial activity of Ga(NO3)3 (GaN), Ga(III)-maltolate (GaM), and Ga(III)-protoporphyrin IX (GaPPIX), belonging to the first-, second- and third-generation of Ga(III) formulations, respectively, on ESKAPE species, including reference strains and multidrug-resistant (MDR) clinical isolates. In addition to the standard culture medium Mueller Hinton broth (MHB), iron-depleted MHB (DMHB) and RPMI-1640 supplemented with 10% human serum (HS) (RPMI-HS) were also included in Ga(III)-susceptibility tests, because of their different nutrient and iron contents. All ESKAPE species were resistant to all Ga(III) compounds in MHB and DMHB (MIC > 32 μM), except Staphylococcus aureus and Acinetobacter baumannii, which were susceptible to GaPPIX. Conversely, the antibacterial activity of GaN and GaM was very evident in RPMI-HS, in which the low iron content and the presence of HS better mimic the in vivo environment. In RPMI-HS about 50% of the strains were sensitive (MIC < 32) to GaN and GaM, both compounds showing a similar spectrum of activity, although GaM was more effective than GaN. In contrast, GaPPIX lost its antibacterial activity in RPMI-HS likely due to the presence of albumin, which binds GaPPIX and counteracts its inhibitory effect. We also demonstrated that the presence of multiple heme-uptake systems strongly influences GaPPIX susceptibility in A. baumannii. Interestingly, GaN and GaM showed only a bacteriostatic effect, whereas GaPPIX exerted a bactericidal activity on susceptible strains. Altogether, our findings raise hope for the future development of Ga(III)-based compounds in the treatment of infections caused by multidrug-resistant ESKAPE pathogens.

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Section: Resultsmentioning

confidence: 99%

Antimicrobial Activity of Gallium Compounds on ESKAPE Pathogens

Hijazi

Visaggio

Pirolo

et al. 2018

Front. Cell. Infect. Microbiol.

100

127

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“…Additionally, crosstalk between metals has been described in bacteria. For example, in Enterococcus faecalis a deficiency or excess of iron provokes activation of different regulators, such as LexA and CopY, which are also stimulated by copper and zinc treatments (Latorre et al, 2018).…”

Section: Intracellular Levels Of Iron Copper Andmentioning

confidence: 99%

Role of the Dihydrodipicolinate Synthase DapA1 on Iron Homeostasis During Cyanide Assimilation by the Alkaliphilic Bacterium Pseudomonas pseudoalcaligenes CECT5344

et al. 2020

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“…Here, we propose a model in which upregulation of the glycerol importer ( glpF2 ), alpha-glycerophosphate oxidase ( glpO ), and glycerol kinase ( glpK ) is driven by the presence of increased intracellular Fe. Consistent with this idea, an E. faecalis V583 fur deletion mutant is incapable of repressing iron uptake, and when grown in iron supplemented media, displayed significantly increased transcription of glycerol dehydrogenase and glycerol kinase ( glpK ) (58). The relationship between glycerol catabolism and Fe availability is unclear at this time.…”

Section: Discussionmentioning

confidence: 75%

Enterococcus faecalis manganese exporter MntE alleviates manganese toxicity and is required for mouse gastrointestinal colonization

Lam

Wong

Chong

et al. 2020

Preprint

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26Bacterial pathogens encounter a variety of nutritional environments in the human host, 27 including nutrient metal restriction and overload. Uptake of manganese (Mn) is essential for 28 Enterococcus faecalis growth and virulence; however, it is not known how this organism 29 prevents Mn toxicity. In this study, we examine the role of the highly conserved MntE 30 transporter in E. faecalis Mn homeostasis and virulence. We show that inactivation of mntE 31 results in growth restriction in the presence of excess Mn, but not other metals, demonstrating 32 its specific role in Mn detoxification. Upon growth in the presence of excess Mn, an mntE 33 mutant accumulates intracellular Mn, iron (Fe), and magnesium (Mg), supporting a role for 34 MntE in Mn and Fe export, and a role for Mg in offsetting Mn toxicity. Growth of the mntE 35 mutant in excess Fe also results in increased levels of intracellular Fe, but not Mn or Mg, 36 providing further support for MntE in Fe efflux. Inactivation of mntE in the presence of 37 excess iron also results in the upregulation of glycerol catabolic genes and enhanced biofilm 38 growth, and addition of glycerol is sufficient to augment biofilm growth for both the mntE 39 mutant and its wild type parental strain, demonstrating that glycerol availability significantly 40 enhances biofilm formation. Finally, we show that mntE contributes to infection of the 41 antibiotic-treated mouse gastrointestinal (GI) tract, suggesting that E. faecalis encounters 42 excess Mn in this niche. Collectively, these findings demonstrate that the manganese exporter 43 MntE plays a crucial role in E. faecalis metal homeostasis and virulence. 44 45 nutritional immunity (1, 4-6). To counteract these host-mediated defences, many bacterial 51 pathogens including Enterococci encode dedicated systems to acquire Mn. 52 53Bacteria encode conserved ABC and NRAMP-family transporters for manganese uptake (1, 54 2). In Enterococcus faecalis, three manganese uptake systems have been described: the ABC-55 type transporter encoded by efaCBA and two NRAMP transporters encoded by mntH1 and 56 mntH2 (7). These three Mn transport systems are functionally redundant since deletion of all 57 three transporter systems (efaCBA, mntH1, mntH2) is required to abrogate intracellular Mn 58 accumulation, rendering the triple mutant severely impaired in growth (7). Furthermore, 59 deletion of both efaCBA and mntH2, or all three transporters together results in attenuated 60 colonization in rabbit endocarditis and mouse catheter-associated urinary tract infection 61 (CAUTI) models (7). Together these observations demonstrate that the ability to acquire Mn 62 is essential for E. faecalis virulence. 64In contrast to Mn influx mechanisms that have been characterized in E. faecalis, Mn export 65 pathways have not been described. The contribution of Mn export to bacterial pathogenesis 66 and virulence has been demonstrated for some bacterial species (8-15) and is dependent on 67 two widely characterized classes of exporters -MntE, a cat...

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The Role of Fur in the Transcriptional and Iron Homeostatic Response of Enterococcus faecalis

Cited by 26 publications

References 63 publications

Antimicrobial Activity of Gallium Compounds on ESKAPE Pathogens

Antimicrobial Activity of Gallium Compounds on ESKAPE Pathogens

Role of the Dihydrodipicolinate Synthase DapA1 on Iron Homeostasis During Cyanide Assimilation by the Alkaliphilic Bacterium Pseudomonas pseudoalcaligenes CECT5344

Enterococcus faecalis manganese exporter MntE alleviates manganese toxicity and is required for mouse gastrointestinal colonization

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