Vitamin B12transports modified RNA intoE. coliandS.Typhimurium cells

Giedyk, Maciej; Jackowska, Agnieszka; Równicki, Marcin; Kolanowska, Monika; Trylska, Joanna; Gryko, Dorota

doi:10.1039/c8cc05064c

Cited by 27 publications

(20 citation statements)

References 33 publications

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“…The TBDTs can be also hijacked by colicins [5], bacteriophages [6], and sideromycins [7] to enter the bacterial cells. Recently, we have shown that vitamin B 12 delivers peptide nucleic acid and 2'O-methyl RNA oligomers into E. coli and S. Typhimurium cells [8][9][10][11]. Thus, vitamin B 12 may be used as a carrier of various oligonucleotides to bacterial cells.…”

Section: Introductionmentioning

confidence: 99%

Extracellular loops of BtuB facilitate transport of vitamin B12 through the outer membrane of E. coli

Pieńko

Trylska

2020

PLoS Comput Biol

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Vitamin B 12 (or cobalamin) is an enzymatic cofactor essential both for mammals and bacteria. However, cobalamin can be synthesized only by few microorganisms so most bacteria need to take it up from the environment through the TonB-dependent transport system. The first stage of cobalamin import to E. coli cells occurs through the outer-membrane receptor called BtuB. Vitamin B 12 binds with high affinity to the extracellular side of the BtuB protein. BtuB forms a β-barrel with inner luminal domain and extracellular loops. To mechanically allow for cobalamin passage, the luminal domain needs to partially unfold with the help of the inner-membrane TonB protein. However, the mechanism of cobalamin permeation is unknown. Using all-atom molecular dynamics, we simulated the transport of cobalamin through the BtuB receptor embedded in an asymmetric and heterogeneous E. coli outermembrane. To enhance conformational sampling of the BtuB loops, we developed the Gaussian force-simulated annealing method (GF-SA) and coupled it with umbrella sampling. We found that cobalamin needs to rotate in order to permeate through BtuB. We showed that the mobility of BtuB extracellular loops is crucial for cobalamin binding and transport and resembles an induced-fit mechanism. Loop mobility depends not only on the position of cobalamin but also on the extension of luminal domain. We provided atomistic details of cobalamin transport through the BtuB receptor showing the essential role of the mobility of BtuB extracellular loops. A similar TonB-dependent transport system is used also by many other compounds, such as haem and siderophores, and importantly, can be hijacked by natural antibiotics. Our work could have implications for future delivery of antibiotics to bacteria using this transport system.

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Section: Introductionmentioning

confidence: 99%

Extracellular loops of BtuB facilitate transport of vitamin B12 through the outer membrane of E. coli

Pieńko

Trylska

2020

PLoS Comput Biol

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“…In this context, the pivotal challenges are the resistance of oligonucleotides to the nuclease digestion, the capability to penetrate bacterial cells, and the efficiency of interaction with a target bacterial molecule. To solve the problem of cell penetration, we coupled antibacterial oligonucleotide constructs with cell delivery agents (Good, 2003; Good and Stach, 2011; Giedyk et al, 2019). Four peptides were chosen as transporters: 19-mer fragment CM18 of cecropin-A/melittin hybrid peptide capable to disturb membrane (Salomone et al, 2013; Fasoli et al, 2014); 15-mer fragment of HGP peptide of gp41 HIV protein, which enhances endosomolytic activity (Kwon et al, 2008; Kwon et al, 2010); 16-mer oligohistidine peptide (Н 16 ) (Iwasaki et al, 2015); and 17-mer analog of bombolytine V, membrane-destroying antimicrobial peptide (AMP), with all basic residues replaced by the glutamine acid (Ahmad et al, 2015).…”

Section: Resultsmentioning

confidence: 99%

Novel Peptide Conjugates of Modified Oligonucleotides for Inhibition of Bacterial RNase P

et al. 2019

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Novel alternatives to traditional antibiotics are now of great demand for the successful treatment of microbial infections. Here, we present the engineering and properties of new oligonucleotide inhibitors of RNase P, an essential bacterial enzyme. The series of 2’- O -methyl RNA (2’-OMe-RNA) and phosphoryl guanidine oligonucleotides were targeted to the substrate-binding region of M1 RNA subunit of the RNase P. Uniformly modified 2’-OMe RNA and selectively modified phosphoryl guanidine oligonucleotides possessed good stability in biological media and effectively inhibited RNase P. Their conjugates with transporting peptides were shown to penetrate bacterial cells ( Escherichia coli and Acinetobacter baumannii ) and inhibit bacterial growth.

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“…The obstacle that mostly limits the adjuvant potential of antisense oligonucleotides is the highly impermeable bacterial membrane [184]. Besides, bacteria do not initiatively uptake oligonucleotides from their environment [185]. Therefore, conjugation with vectors such as lipids [186], cell-penetrating peptides [187], polymers [188], and nanoparticles [189] would facilitate the delivery of antisense oligonucleotides to various bacterial cells.…”

Section: Bacterial Resistance Enzymes Inhibitorsmentioning

confidence: 99%

Molecules that Inhibit Bacterial Resistance Enzymes

Liu

Xiao

et al. 2018

Molecules

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Antibiotic resistance mediated by bacterial enzymes constitutes an unmet clinical challenge for public health, particularly for those currently used antibiotics that are recognized as “last-resort” defense against multidrug-resistant (MDR) bacteria. Inhibitors of resistance enzymes offer an alternative strategy to counter this threat. The combination of inhibitors and antibiotics could effectively prolong the lifespan of clinically relevant antibiotics and minimize the impact and emergence of resistance. In this review, we first provide a brief overview of antibiotic resistance mechanism by bacterial secreted enzymes. Furthermore, we summarize the potential inhibitors that sabotage these resistance pathways and restore the bactericidal activity of inactive antibiotics. Finally, the faced challenges and an outlook for the development of more effective and safer resistance enzyme inhibitors are discussed.

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Vitamin B₁₂transports modified RNA intoE. coliandS.Typhimurium cells

Abstract: Vitamin B12 can transport oligonucleotides into Escherichia coli and Salmonella typhimurium cells.

Cited by 27 publications

References 33 publications

Extracellular loops of BtuB facilitate transport of vitamin B12 through the outer membrane of E. coli

Extracellular loops of BtuB facilitate transport of vitamin B12 through the outer membrane of E. coli

Novel Peptide Conjugates of Modified Oligonucleotides for Inhibition of Bacterial RNase P

Molecules that Inhibit Bacterial Resistance Enzymes

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