Energy‐Coupling Factor Transporters as Novel Antimicrobial Targets

Bousis, Spyridon; Setyawati, Inda; Diamanti, Eleonora; Slotboom, Dirk Jan; Hirsch, Anna K. H.

doi:10.1002/adtp.201800066

Cited by 26 publications

(42 citation statements)

References 108 publications

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“…However, analysis revealed with high confidence the transporter gene cytX in all R. inulinivorans genomes that carries hydroxymethylpyrimidine [ 114 ], which can then be converted into a precursor for thiamine with the bifunctional enzyme thiD . Additionally, we found evidence for a thiamine energy coupling factor (ECF) transporter [ 115 ], thiT , in all species except R. faecis .…”

Section: Resultsmentioning

confidence: 99%

Comparative genomics of the genus Roseburia reveals divergent biosynthetic pathways that may influence colonic competition among species

et al. 2020

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Roseburia species are important denizens of the human gut microbiome that ferment complex polysaccharides to butyrate as a terminal fermentation product, which influences human physiology and serves as an energy source for colonocytes. Previous comparative genomics analyses of the genus Roseburia have examined polysaccharide degradation genes. Here, we characterize the core and pangenomes of the genus Roseburia with respect to central carbon and energy metabolism, as well as biosynthesis of amino acids and B vitamins using orthology-based methods, uncovering significant differences among species in their biosynthetic capacities. Variation in gene content among Roseburia species and strains was most significant for cofactor biosynthesis. Unlike all other species of Roseburia that we analysed, Roseburia inulinivorans strains lacked biosynthetic genes for riboflavin or pantothenate but possessed folate biosynthesis genes. Differences in gene content for B vitamin synthesis were matched with differences in putative salvage and synthesis strategies among species. For example, we observed extended biotin salvage capabilities in R. intestinalis strains, which further suggest that B vitamin acquisition strategies may impact fitness in the gut ecosystem. As differences in the functional potential to synthesize components of biomass (e.g. amino acids, vitamins) can drive interspecies interactions, variation in auxotrophies of the Roseburia spp. genomes may influence in vivo gut ecology. This study serves to advance our understanding of the potential metabolic interactions that influence the ecology of Roseburia spp. and, ultimately, may provide a basis for rational strategies to manipulate the abundances of these species.

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Section: Resultsmentioning

confidence: 99%

Comparative genomics of the genus Roseburia reveals divergent biosynthetic pathways that may influence colonic competition among species

et al. 2020

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“…ECF transporter complexes have recently gained renewed attention with the identification of a novel haem transporter belonging to the family of ECF-type ABC transporters (34)(35)(36). As various ECF transporters complexes are encoded in the genome of various human pathogens but not in humans (37,38), it makes them attractive targets for newly designed antimicrobial compounds, for which this work represents a stepping stone towards studying their means of action on a structural level.…”

Section: Discussionmentioning

confidence: 99%

Insights into the bilayer-mediated toppling mechanism of a folate-specific ECF transporter by cryo-EM

Thangaratnarajah

Rheinberger

Slotboom

2021

Proc. Natl. Acad. Sci. U.S.A.

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Energy-coupling factor (ECF)–type transporters are small, asymmetric membrane protein complexes (∼115 kDa) that consist of a membrane-embedded, substrate-binding protein (S component) and a tripartite ATP-hydrolyzing module (ECF module). They import micronutrients into bacterial cells and have been proposed to use a highly unusual transport mechanism, in which the substrate is dragged across the membrane by a toppling motion of the S component. However, it remains unclear how the lipid bilayer could accommodate such a movement. Here, we used cryogenic electron microscopy at 200 kV to determine structures of a folate-specific ECF transporter in lipid nanodiscs and detergent micelles at 2.7- and 3.4-Å resolution, respectively. The structures reveal an irregularly shaped bilayer environment around the membrane-embedded complex and suggest that toppling of the S component is facilitated by protein-induced membrane deformations. In this way, structural remodeling of the lipid bilayer environment is exploited to guide the transport process.

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“…Transporters from the ECF family, which are not present in humans, have been proposed as potential antimicrobial targets. Assessment of the likelihood to find a selective, low-molecular weight molecule that binds with high affinity to the target, which is usually referred to as druggability assessment, identified up to twelve druggable pockets within a reference ECF transporter system [63]. An alternative approach to prevent metal acquisition could be either the inhibition of binding of the S-components to the ECF module or the inhibition of their ability to bind metals.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional response to metal starvation in the emerging pathogen Mycoplasma genitalium is mediated by Fur-dependent and –independent regulatory pathways

Martínez-Torró

Torres-Puig

Monge³

et al. 2019

Emerging Microbes & Infections

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Transition metals participate in numerous enzymatic reactions and they are essential for survival in all living organisms. For this reason, bacterial pathogens have evolved dedicated machineries to effectively compete with their hosts and scavenge metals at the site of infection. In this study, we investigated the mechanisms controlling metal acquisition in the emerging human pathogen Mycoplasma genitalium. We observed a robust transcriptional response to metal starvation, and many genes coding for predicted lipoproteins and ABC-transporters were significantly up-regulated. Transcriptional analysis of a mutant strain lacking a metalloregulator of the Fur family revealed the activation of a full operon encoding a putative metal transporter system and a gene coding for a Histidine-rich lipoprotein (Hrl). We recognized a conserved sequence with dyad symmetry within the promoter region of the Fur-regulated genes. Mutagenesis of the predicted Fur operator within the hrl promoter abrogated Fur-and metal-dependent expression of a reporter gene. Metal starvation still impelled a strong transcriptional response in the fur mutant, demonstrating the existence of Fur-independent regulatory pathways controlling metal homeostasis. Finally, analysis of metal accumulation in the wild-type strain and the fur mutant by ICP-MS revealed an important role of Fur in nickel acquisition.

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Energy‐Coupling Factor Transporters as Novel Antimicrobial Targets

Cited by 26 publications

References 108 publications

Comparative genomics of the genus Roseburia reveals divergent biosynthetic pathways that may influence colonic competition among species

Comparative genomics of the genus Roseburia reveals divergent biosynthetic pathways that may influence colonic competition among species

Insights into the bilayer-mediated toppling mechanism of a folate-specific ECF transporter by cryo-EM

Transcriptional response to metal starvation in the emerging pathogen Mycoplasma genitalium is mediated by Fur-dependent and –independent regulatory pathways

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