Encapsulated Methionine γ-Lyase: Application in Enzyme Prodrug Therapy of <i>Pseudomonas aeruginosa</i> Infection

Morozova, Elena A.; Kulikova, Vitalia V.; Koval, V. P.; Anufrieva, Natalya V.; Chernukha, M.; Avetisyan, L.; Лебедева, Л. Н.; Medvedeva, O.; Бурмистров, Е. М.; Shaginyan, I.A.; Revtovich, Svetlana V.; Demidkina, Tatyana V.

doi:10.1021/acsomega.9b03555

Cited by 7 publications

(6 citation statements)

References 32 publications

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“…We have shown that the inclusion of C115H MGL into polyionic vesicles significantly improved its pharmacokinetic characteristics . Therapeutic efficacy of the “pharmacological pairs” composed of C115H MGL PICsomes and the substrates S -substituted l -cysteine sulfoxides has been demonstrated against the murine model of experimental sepsis caused by the multidrug-resistant Pseudomonas aeruginosa 203–2 strain …”

Section: Introductionmentioning

confidence: 98%

“…27 Therapeutic efficacy of the "pharmacological pairs" composed of C115H MGL PICsomes and the substrates S-substituted L-cysteine sulfoxides has been demonstrated against the murine model of experimental sepsis caused by the multidrug-resistant Pseudomonas aeruginosa 203−2 strain. 28 Here, we studied the influence of the molecular weight of polyaspartic acid (pAsp) and polylysine (pLys), their concentration, enzyme concentration, and availability of dextran on the PICsome size, their tendency to agglomerate, encapsulation degree of the enzymes, and their release from the vesicles. Steady-state parameters of the βand γelimination reactions catalyzed by encapsulated mutant enzymes were determined.…”

Section: Introductionmentioning

confidence: 99%

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Characteristics and Stability Assessment of Therapeutic Methionine γ-lyase-Loaded Polyionic Vesicles

et al. 2021

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Pyridoxal 5′-phosphate-dependent methionine γ-lyase from Citrobacter freundii (MGL, EC 4.4.1.11) is studied as an antitumor enzyme and in combination with substrates as an antibacterial agent in enzyme pro-drug therapy. For the possibility of in vivo trials, two mutant forms, C115H MGL and V358Y MGL, were encapsulated into polyionic vesicles (PICsomes). Five pairs of polymers with the number of polymer chain units 20, 50, 70, 120, and 160 were synthesized. The effect of polymer lengthPEGylated poly-l-aspartic acid and poly-l-lysineon the degree of MGL incorporation into PICsomes and their size was investigated. Encapsulation of proteins in PICsomes is a rather new technique. Our data demonstrated that the length of the polymers and, therefore, the ratio of the hydrophobic and hydrophilic fragments most likely should be selected individually for each protein to be encapsulated. The efficiency of encapsulation of MGL mutant forms into PICsomes was up to 11%. The hydrodynamic diameter and surface potential of hollow and MGL-loaded PICsomes were evaluated by the dynamic light scattering method. The size and morphology of the PICsomes were determined by atomic force microscopy. The most acceptable for further in vivo studies were PICsomes20 with a size of 57–64 nm, PICsomes70 of 50–90 nm, and PICsomes120 of 100–105 nm. The analysis of the steady-state parameters has demonstrated that both mutant forms retained their catalytic properties inside the nanoparticles. The release study of the enzymes from PICsomes revealed that about 50% of the enzymes remained encapsulated in PICsomes70 and PICsomes120 after 24 h. Based on the data obtained, the most promising for in vivo studies are PICsomes70 and PICsomes120.

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Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Characteristics and Stability Assessment of Therapeutic Methionine γ-lyase-Loaded Polyionic Vesicles

et al. 2021

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“…Instead, to succeed in the production of the enzyme prodrug therapy for anticandidal therapeutic purposes, we propose to use another closely related to alliinase enzyme (Figure 1). Recently, we have shown that a binary system of methionine γ-lyase (EC 4.4.1.11, MGL)/S-alk(en)yl-L-cysteine sulfoxides possesses antimicrobial activity in vitro and in vivo [13,14]. This system generates antipathogenic compounds both from natural sub- Recently, we have shown that a binary system of methionine γ-lyase (EC 4.4.1.11, MGL)/S-alk(en)yl-L-cysteine sulfoxides possesses antimicrobial activity in vitro and in vivo [13,14].…”

Section: Introductionmentioning

confidence: 99%

“…Recently, we have shown that a binary system of methionine γ-lyase (EC 4.4.1.11, MGL)/S-alk(en)yl-L-cysteine sulfoxides possesses antimicrobial activity in vitro and in vivo [13,14]. This system generates antipathogenic compounds both from natural sub- Recently, we have shown that a binary system of methionine γ-lyase (EC 4.4.1.11, MGL)/S-alk(en)yl-L-cysteine sulfoxides possesses antimicrobial activity in vitro and in vivo [13,14]. This system generates antipathogenic compounds both from natural substrates and from their synthetic analogues, and the core enzyme can maintain its activity at the targeted surface via encapsulation.…”

Section: Introductionmentioning

confidence: 99%

Anticandidal Activity of In Situ Methionine γ-Lyase-Based Thiosulfinate Generation System vs. Synthetic Thiosulfinates

Revtovich,

Lyfenko,

Tkachev

et al. 2023

Pharmaceuticals

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Candida albicans and non-albicans Candida species are a common cause of human mucosal infections, as well as bloodstream infections and deep mycoses. The emergence of resistance of Candida spp. to antifungal drugs used in practice requires the search for new antimycotics. The present study unravels the antifungal potential of the synthetic dialk(en)ylthiosulfinates in comparison with an enzymatic in situ methionine γ-lyase-based thiosulfinate generation system (TGS). The kinetics of the TGS reaction, namely, the methionine γ-lyase-catalyzed β-elimination of S-alk(en)yl-L-cysteine sulfoxides, was investigated via 1H NMR spectroscopy for the first time, revealing fast conversion rates and the efficient production of anticandidal dialk(en)ylthiosulfinates. The anticandidal potential of this system vs. synthetic thiosulfinates was investigated through an in vitro assay. TGS proved to be more effective (MIC range 0.36–1.1 μg/mL) than individual substances (MIC range 0.69–3.31 μg/mL). The tested preparations had an additive effect with the commercial antimycotics fluconazole, amphotericin B and 5-flucytosine demonstrating a fractional inhibitory coefficient index in the range of 0.5–2 μg/mL. TGS can be regarded as an attractive candidate for the targeted delivery of antimycotic thiosulfinates and for further implementation onto medically implanted devices.

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“…In addition, antibiotic-free nanoreactors have recently been designed, based on the in situ conversion of prodrugs. For example, the conversion of (±) S -alk(en)yl- L -cysteine sulfoxides into antibacterial thiosulfinates have shown promise as a treatment against P. aeruginosa . Nanoreactors, and other catalytic systems, utilizing the activity of GOX and peroxidase enzymes (or mimics) represent a particularly effective antibacterial strategy against various species of Gram-positive and Gram-negative bacteria, producing reactive antimicrobial species such as H 2 O 2 , – OCl, or hydroxyl radicals ( • OH) in response to the presence of glucose. ,, However, using simple, well-defined systems and achieving controlled and local action of such nanoreactors remains challenging.…”

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confidence: 99%

Controlled Dendrimersome Nanoreactor System for Localized Hypochlorite-Induced Killing of Bacteria

et al. 2020

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Antibiotic resistance is a serious global health problem necessitating new bactericidal approaches such as nanomedicines. Dendrimersomes (DSs) have recently become a valuable alternative nanocarrier to polymersomes and liposomes due to their molecular definition and synthetic versatility. Despite this, their biomedical application is still in its infancy. Inspired by the localized antimicrobial function of neutrophil phagosomes and the versatility of DSs, a simple three-component DS-based nanoreactor with broad-spectrum bactericidal activity is presented. This was achieved by encapsulation of glucose oxidase (GOX) and myeloperoxidase (MPO) within DSs (GOX-MPO-DSs), self-assembled from an amphiphilic Janus dendrimer, that possesses a semipermeable membrane. By external addition of glucose to GOX-MPO-DS, the production of hypochlorite ( − OCl), a highly potent antimicrobial, by the enzymatic cascade was demonstrated. This cascade nanoreactor yielded a potent bactericidal effect against two important multidrug resistant pathogens, Staphylococcus aureus ( S. aureus ) and Pseudomonas aeruginosa ( P. aeruginosa ), not observed for H 2 O 2 producing nanoreactors, GOX-DS. The production of highly reactive species such as – OCl represents a harsh bactericidal approach that could also be cytotoxic to mammalian cells. This necessitates the development of strategies for activating – OCl production in a localized manner in response to a bacterial stimulus. One option of locally releasing sufficient amounts of substrate using a bacterial trigger (released toxins) was demonstrated with lipidic glucose-loaded giant unilamellar vesicles (GUVs), envisioning, e.g ., implant surface modification with nanoreactors and GUVs for localized production of bactericidal agents in the presence of bacterial growth.

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Encapsulated Methionine γ-Lyase: Application in Enzyme Prodrug Therapy of Pseudomonas aeruginosa Infection

Cited by 7 publications

References 32 publications

Characteristics and Stability Assessment of Therapeutic Methionine γ-lyase-Loaded Polyionic Vesicles

Characteristics and Stability Assessment of Therapeutic Methionine γ-lyase-Loaded Polyionic Vesicles

Anticandidal Activity of In Situ Methionine γ-Lyase-Based Thiosulfinate Generation System vs. Synthetic Thiosulfinates

Controlled Dendrimersome Nanoreactor System for Localized Hypochlorite-Induced Killing of Bacteria

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