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1.
J Inorg Biochem ; 256: 112572, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38691971

ABSTRACT

Recognizing that metal ions play an important role in modifying the pharmacological properties of known organic-based drugs, the present manuscript addresses the complexation of the antifungal agent voriconazole (vcz) with the biologically relevant silver(I) ion as a strategy for the development of new antimycotics. The synthesized silver(I) complexes with vcz were characterized by mass spectrometry, IR, UV-Vis and NMR spectroscopy and single-crystal X-ray diffraction analysis. The crystallographic results showed that complexes {[Ag(vcz)(H2O)]CH3SO3}n (1), {[Ag(vcz)2]BF4}n (2) and {[Ag(vcz)2]PF6}n (3) have polymeric structures in the solid state, in which silver(I) ions have a distorted tetrahedral geometry. On the other hand, DFT calculations revealed that the investigated silver(I) complexes 1-3 in DMSO exist as linear [Ag(vcz-N2)(vcz-N19)]+ (1a), [Ag(vcz-N2)(vcz-N4)]+ (2a) and [Ag(vcz-N4)2]+ (3a) species, respectively. The evaluated complexes showed an enhanced anti-Candida activity compared to the parent drug with minimal inhibitory concentration (MIC) values in the range of 0.02-1.05 µM. In comparison with vcz, the corresponding silver(I) complexes showed better activity in prevention hyphae and biofilm formation of C. albicans, indicating that they could be considered as promising agents against Candida that significantly inhibit its virulence. Also, these complexes are much better inhibitors of ergosterol synthesis in the cell membrane of C. albicans at the concentration of 0.5 × MIC. This is also confirmed by a molecular docking, which revealed that complexes 1a - 3a showed better inhibitory activity than vcz against the sterol 14α-demethylase enzyme cytochrome P450 (CYP51B), which plays a crucial role in the formation of ergosterol.


Subject(s)
Antifungal Agents , Coordination Complexes , Microbial Sensitivity Tests , Silver , Voriconazole , Antifungal Agents/pharmacology , Antifungal Agents/chemistry , Antifungal Agents/chemical synthesis , Voriconazole/pharmacology , Voriconazole/chemistry , Silver/chemistry , Silver/pharmacology , Coordination Complexes/pharmacology , Coordination Complexes/chemistry , Coordination Complexes/chemical synthesis , Candida albicans/drug effects , Candida/drug effects , Crystallography, X-Ray
2.
Front Bioeng Biotechnol ; 12: 1351583, 2024.
Article in English | MEDLINE | ID: mdl-38807651

ABSTRACT

Bacterial natural products (BNPs) are very important sources of leads for drug development and chemical novelty. The possibility to perform late-stage diversification of BNPs using biocatalysis is an attractive alternative route other than total chemical synthesis or metal complexation reactions. Although biocatalysis is gaining popularity as a green chemistry methodology, a vast majority of orphan sequenced genomic data related to metabolic pathways for BNP biosynthesis and its tailoring enzymes are underexplored. In this review, we report a systematic overview of biotransformations of 21 molecules, which include derivatization by halogenation, esterification, reduction, oxidation, alkylation and nitration reactions, as well as degradation products as their sub-derivatives. These BNPs were grouped based on their biological activities into antibacterial (5), antifungal (5), anticancer (5), immunosuppressive (2) and quorum sensing modulating (4) compounds. This study summarized 73 derivatives and 16 degradation sub-derivatives originating from 12 BNPs. The highest number of biocatalytic reactions was observed for drugs that are already in clinical use: 28 reactions for the antibacterial drug vancomycin, followed by 18 reactions reported for the immunosuppressive drug rapamycin. The most common biocatalysts include oxidoreductases, transferases, lipases, isomerases and haloperoxidases. This review highlights biocatalytic routes for the late-stage diversification reactions of BNPs, which potentially help to recognize the structural optimizations of bioactive scaffolds for the generation of new biomolecules, eventually leading to drug development.

3.
Dalton Trans ; 53(5): 2218-2230, 2024 Jan 30.
Article in English | MEDLINE | ID: mdl-38193719

ABSTRACT

Inspired by the emergence of resistance to currently available antifungal therapy and by the great potential of metal complexes for the treatment of various diseases, we synthesized three new silver(I) complexes containing clinically used antifungal azoles as ligands, [Ag(ecz)2]SbF6 (1, ecz is econazole), {[Ag(vcz)2]SbF6}n (2, vcz is voriconazole), and [Ag(ctz)2]SbF6 (3, ctz is clotrimazole), and investigated their antimicrobial properties. The synthesized complexes were characterized by mass spectrometry, IR, UV-vis and 1H NMR spectroscopy, cyclic voltammetry, and single-crystal X-ray diffraction analysis. In the mononuclear complexes 1 and 3 with ecz and ctz, respectively, the silver(I) ion has the expected linear geometry, in which the azoles are monodentately coordinated to this metal center through the N3 imidazole nitrogen atom. In contrast, the vcz-containing complex 2 has a polymeric structure in the solid state in which the silver(I) ions are coordinated by four nitrogen atoms in a distorted tetrahedral geometry. DFT calculations were done to predict the most favorable structures of the studied complexes in DMSO solution. All the studied silver(I) complexes have shown excellent antifungal and good to moderate antibacterial activities with minimal inhibitory concentration (MIC) values in the ranges of 0.01-27.1 and 2.61-47.9 µM on the selected panel of fungi and bacteria, respectively. Importantly, the complexes 1-3 have exhibited a significantly improved antifungal activity compared to the free azoles, with the most pronounced effect observed in the case of complex 2 compared to the parent vcz against Candida glabrata with an increase of activity by five orders of magnitude. Moreover, the silver(I)-azole complexes 2 and 3 significantly inhibited the formation of C. albicans hyphae and biofilms at the subinhibitory concentration of 50% MIC. To investigate the impact of the complex 3 more thoroughly on Candida pathogenesis, its effect on the adherence of C. albicans to A549 cells (human adenocarcinoma alveolar basal epithelial cells), as an initial step of the invasion of host cells, was studied.


Subject(s)
Coordination Complexes , Silver , Humans , Silver/pharmacology , Silver/chemistry , Candida , Antifungal Agents/pharmacology , Antifungal Agents/chemistry , Azoles/pharmacology , Candida albicans , Microbial Sensitivity Tests , Ions/pharmacology , Nitrogen , Coordination Complexes/pharmacology , Coordination Complexes/chemistry
4.
Appl Microbiol Biotechnol ; 108(1): 185, 2024 Jan 30.
Article in English | MEDLINE | ID: mdl-38289383

ABSTRACT

The application of enzymes is expanding across diverse industries due to their nontoxic and biodegradable characteristics. Another advantage is their cost-effectiveness, reflected in reduced processing time, water, and energy consumption. Although Gram-positive bacteria, Bacillus, and Streptomyces spp. are successfully used for production of industrially relevant enzymes, they still lag far behind Escherichia coli as hosts for recombinant protein production. Generally, proteins secreted by Bacillus and Streptomyces hosts are released into the culture medium; their native conformation is preserved and easier recovery process enabled. Given the resilience of both hosts in harsh environmental conditions and their spore-forming capability, a deeper understanding and broader use of Bacillus and Streptomyces as expression hosts could significantly enhance the robustness of industrial bioprocesses. This mini-review aims to compare two expression hosts, emphasizing their specific advantages in industrial surroundings such are chemical, detergent, textile, food, animal feed, leather, and paper industries. The homologous sources, heterologous hosts, and molecular tools used for the production of recombinant proteins in these hosts are discussed. The potential to use both hosts as biocatalysts is also evaluated. Undoubtedly, Bacillus and Streptomyces spp. as production hosts possess the potential to take on a more substantial role, providing superior (bio-based) process robustness and flexibility. KEY POINTS: • Bacillus and Streptomyces spp. as robust hosts for enzyme production. • Industrially relevant enzyme groups for production in alternative hosts highlighted. • Molecular biology techniques are enabling easier utilization of both hosts.


Subject(s)
Bacillus , Animals , Bacillus/genetics , Animal Feed , Biological Transport , Culture Media , Escherichia coli
5.
ACS Infect Dis ; 9(10): 1941-1948, 2023 Oct 13.
Article in English | MEDLINE | ID: mdl-37655776

ABSTRACT

The ambigols are cyanobacterial natural products characterized by three polychlorinated aromatic building blocks connected by biaryl and biaryl ether bridges. All ambigols known to date possess promising biological activities. Most significantly, ambigol A was reported to have antibacterial activity against Gram-positive bacteria, such as Bacillus megaterium and B. subtilis. We established a diverse compound library for in-depth biological evaluation building on our previous bio- and total synthetic research on this natural product family. To explore the antimicrobial potential in detail and to determine initial structure-activity relationships of this product class, a large set of dimeric and trimeric compounds were screened against selected bacterial and Candida target strains. Our results reveal exceptional antibiotic activity of the ambigols, especially against challenging clinical isolates.

6.
J Org Chem ; 88(19): 14184-14188, 2023 10 06.
Article in English | MEDLINE | ID: mdl-37708429

ABSTRACT

The myxobacterial natural product myxocoumarin A from Stigmatella aurantiaca MYX-030 has remarkable antifungal activity against agriculturally relevant pathogens. To broaden the initial evaluation of its biological potential, we herein completed the first total synthesis of myxocoumarin A. This synthetic access facilitated stereochemical investigations on the natural product structure, revealing its (R)-configuration. Biological activity profiling showed a lack of activity against Candida spp. and Gram-negative bacteria but revealed strong antibiotic activities against Bacillus subtilis and Staphylococcus aureus, including MRSA.


Subject(s)
Anti-Infective Agents , Biological Products , Microbial Sensitivity Tests , Anti-Infective Agents/pharmacology , Antifungal Agents/chemistry , Anti-Bacterial Agents/chemistry
7.
Enzyme Microb Technol ; 171: 110322, 2023 Dec.
Article in English | MEDLINE | ID: mdl-37722241

ABSTRACT

Phenazines, including pyocyanin (PYO) and 1-hydroxyphenazine (1-HP) are extracellular secondary metabolites and multifunctional pigments of Pseudomonas aeruginosa responsible for its blue-green color. These versatile molecules are electrochemically active, involved in significant biological activities giving fitness to the host, but also recognized as antimicrobial and anticancer agents. Their wider application is still limited partly due to the cost of carbon substrate for production, which can be solved by the utilization of carbon from food waste within the biorefinery concept. In this study, a variety of food waste streams (banana peel, potato peel, potato washing, stale bread, yoghurt, processed meat, boiled eggs and mixed canteen waste) was used as sole nutrient source in submerged cultures of P. aeruginosa BK25H. Stale bread was identified as the most suitable substrate to support phenazine biopigments production and bacterial growth. This was further increased in 5-liter fermenter when on average 5.2 mg L-1 of PYO and 4.4 mg L-1 of 1-HP were purified after 24 h batch cultivations from the fermentation medium consisting of homogenized stale bread in tap water. Purified biopigments showed moderate antimicrobial activity, and showed different toxicity profiles, with PYO not being toxic against Caenorhabditis elegans, a free-living soil nematode up to 300 µg mL-1 and 1-HP showing lethal effects at 75 µg mL-1. Therefore, stale bread waste stream with minimal pretreatment should be considered as suitable biorefinery feedstock, as it can support the production of valuable biopigments such as phenazines.

8.
Chem Biodivers ; 20(4): e202300134, 2023 Apr.
Article in English | MEDLINE | ID: mdl-36898082

ABSTRACT

This is the first report on the separation and biological assessment of all metabolites derived from Pulicaria armena (Asteraceae) which is an endemic species narrowly distributed in the eastern part of Turkey. The phytochemical analysis of P. armena resulted in the identification of one simple phenolic glucoside together with eight flavon and flavonol derivatives whose chemical structures were elucidated by NMR experiments and by the comparison of the spectral data with the relevant literature. The screening of all molecules for their antimicrobial, anti-quorum sensing, and cytotoxic activities revealed the biological potential of some of the isolated compounds. Additionally, quorum sensing inhibitory activity of quercetagetin 5,7,3' trimethyl ether was supported by molecular docking studies in the active site of LasR which is the primary regulator of this cell-to-cell communication system in bacteria. Lastly, the critical molecular properties indicating drug-likeness of the compounds isolated from P. armena were predicted. As microbial infections can be a serious problem for cancer patients with compromised immune systems, this comprehensive phytochemical research on P. armena with its anti-quorum sensing and cytotoxic compounds can provide a new approach to the treatment.


Subject(s)
Anti-Infective Agents , Asteraceae , Flavonoids , Pulicaria , Quorum Sensing , Humans , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Anti-Infective Agents/chemistry , Anti-Infective Agents/pharmacology , Asteraceae/chemistry , Flavonoids/chemistry , Flavonoids/pharmacology , Molecular Docking Simulation , Phytochemicals/chemistry , Phytochemicals/metabolism , Phytochemicals/pharmacology , Pulicaria/chemistry , Quorum Sensing/drug effects
9.
RSC Adv ; 13(7): 4376-4393, 2023 Jan 31.
Article in English | MEDLINE | ID: mdl-36744286

ABSTRACT

Dimethyl 6-(pyrazine-2-yl)pyridine-3,4-dicarboxylate (py-2pz) was used as a ligand for the synthesis of new copper(ii) and silver(i) complexes, [CuCl2(py-2pz)]2 (1), [Cu(CF3SO3)(H2O)(py-2pz)2]CF3SO3·2H2O (2), [Ag(py-2pz)2]PF6 (3) and {[Ag(NO3)(py-2pz)]·0.5H2O} n (4). The complexes were characterized by spectroscopic and electrochemical methods, while their structures were determined by single crystal X-ray diffraction analysis. The X-ray analysis revealed the bidentate coordination mode of py-2pz to the corresponding metal ion via its pyridine and pyrazine nitrogen atoms in all complexes, while in polynuclear complex 4, the heterocyclic pyrazine ring of one py-2pz additionally behaves as a bridging ligand between two Ag(i) ions. DFT calculations were performed to elucidate the structures of the investigated complexes in solution. The antimicrobial potential of the complexes 1-4 was evaluated against two bacterial (Pseudomonas aeruginosa and Staphylococcus aureus) and two Candida (C. albicans and C. parapsilosis) species. Silver(i) complexes 3 and 4 have shown good antibacterial and antifungal properties with minimal inhibitory concentration (MIC) values ranging from 4.9 to 39.0 µM (3.9-31.2 µg mL-1). All complexes inhibited the filamentation of C. albicans and hyphae formation, while silver(i) complexes 3 and 4 had also the ability to inhibit the biofilm formation process of this fungus. The binding affinity of the complexes 1-4 with calf thymus DNA (ct-DNA) and bovine serum albumin (BSA) was studied by fluorescence emission spectroscopy to clarify the mode of their antimicrobial activity. Catechol oxidase biomimetic catalytic activity of copper(ii) complexes 1 and 2 was additionally investigated by using 3,5-di-tert-butylcatechol (3,5-DTBC) and o-aminophenol (OAP) as substrates.

10.
Int J Mol Sci ; 23(20)2022 Oct 13.
Article in English | MEDLINE | ID: mdl-36293056

ABSTRACT

Curcumin and triangular silver nanoplates (TSNP)-incorporated bacterial cellulose (BC) films present an ideal antimicrobial material for biomedical applications as they afford a complete set of requirements, including a broad range of long-lasting potency and superior efficacy antimicrobial activity, combined with low toxicity. Here, BC was produced by Komagataeibacter medellinensis ID13488 strain in the presence of curcumin in the production medium (2 and 10%). TSNP were incorporated in the produced BC/curcumin films using ex situ method (21.34 ppm) and the antimicrobial activity was evaluated against Escherichia coli ATCC95922 and Staphylococcus aureus ATCC25923 bacterial strains. Biological activity of these natural products was assessed in cytotoxicity assay against lung fibroblasts and in vivo using Caenorhabditis elegans and Danio rerio as model organisms. Derived films have shown excellent antimicrobial performance with growth inhibition up to 67% for E. coli and 95% for S. aureus. In a highly positive synergistic interaction, BC films with 10% curcumin and incorporated TSNP have shown reduced toxicity with 80% MRC5 cells survival rate. It was shown that only 100% concentrations of film extracts induce low toxicity effect on model organisms' development. The combined and synergistic advanced anti-infective functionalities of the curcumin and TSNP incorporated in BC have a high potential for development for application within the clinical setting.


Subject(s)
Anti-Infective Agents , Biological Products , Curcumin , Metal Nanoparticles , Silver/pharmacology , Cellulose/pharmacology , Curcumin/pharmacology , Staphylococcus aureus , Escherichia coli , Anti-Infective Agents/pharmacology , Anti-Bacterial Agents/pharmacology , Biological Products/pharmacology
11.
J Appl Microbiol ; 133(4): 2560-2568, 2022 Oct.
Article in English | MEDLINE | ID: mdl-35880373

ABSTRACT

AIMS: Sequencing and genome analysis of two co-isolated streptomycetes, named BV410-1 and BV410-10, and the effect of their co-cultivation on the staurosporine production. METHODS AND RESULTS: Identification of two strains through genome sequencing and their separation using different growth media was conducted. Sequence analysis revealed that the genome of BV410-1 was 9.5 Mb, whilst that of BV410-10 was 7.1 Mb. AntiSMASH analysis identified 28 biosynthetic gene clusters (BGCs) from BV410-1, including that responsible for staurosporine biosynthesis, whilst 20 BGCs were identified from BV410-10. The addition of cell-free supernatant from BV410-10 monoculture to BV410-1 fermentations improved the staurosporine yield from 8.35 mg L-1 up to 15.85 mg L-1 , whilst BV410-10 monoculture ethyl acetate extract did not have the same effect. Also, there was no improvement in staurosporine production when artificial mixed cultures were created using three different BV410-1 and BV410-10 spore ratios. CONCLUSIONS: The growth of BV410-10 was inhibited when the two strains were grown together on agar plates. Culture supernatants of BV410-10 showed potential to stimulate staurosporine production in BV410-1, but overall co-cultivation attempts did not restore the previously reported yield of staurosporine produced by the original mixed isolate. SIGNIFICANCE AND IMPACT OF STUDY: This work confirmed complex relations between streptomycetes in soil that are difficult to recreate under the laboratory conditions. Also, mining of streptomycetes genomes that mainly produce known bioactive compounds could still be the fruitful approach in search for novel bioactive molecules.


Subject(s)
Streptomyces , Agar , Multigene Family , Soil , Staurosporine/pharmacology , Streptomyces/genetics
12.
Molecules ; 27(12)2022 Jun 09.
Article in English | MEDLINE | ID: mdl-35744855

ABSTRACT

Prodigiosins (prodiginines) are a class of bacterial secondary metabolites with remarkable biological activities and color. In this study, optimized production, purification, and characterization of prodigiosin (PG) from easily accessible Serratia marcescens ATCC 27117 strain has been achieved to levels of 14 mg/L of culture within 24 h. Furthermore, environmentally friendly bromination of produced PG was used to afford both novel mono- and dibrominated derivatives of PG. PG and its Br derivatives showed anticancer potential with IC50 values range 0.62-17.00 µg/mL for all tested cancer cell lines and induction of apoptosis but low selectivity against healthy cell lines. All compounds did not affect Caenorhabditiselegans at concentrations up to 50 µg/mL. However, an improved toxicity profile of Br derivatives in comparison to parent PG was observed in vivo using zebrafish (Danio rerio) model system, when 10 µg/mL applied at 6 h post fertilization caused death rate of 100%, 30% and 0% by PG, PG-Br, and PG-Br2, respectively, which is a significant finding for further structural optimizations of bacterial prodigiosins. The drug-likeness of PG and its Br derivatives was examined, and the novel Br derivatives obey the Lipinski's "rule of five", with an exemption of being more lipophilic than PG, which still makes them good targets for further structural optimization.


Subject(s)
Neoplasms , Prodigiosin , Animals , Apoptosis , Prodigiosin/metabolism , Prodigiosin/pharmacology , Serratia marcescens/metabolism , Zebrafish/metabolism
13.
Chemistry ; 28(32): e202200394, 2022 Jun 07.
Article in English | MEDLINE | ID: mdl-35229915

ABSTRACT

The increasing emergence of resistances against established antibiotics is a substantial threat to human health. The discovery of new compounds with potent antibiotic activity is thus of utmost importance. Within this work, we identify strong antibiotic activity of the natural product myxocoumarin B from Stigmatella aurantiaca MYX-030 against a range of clinically relevant bacterial pathogens, including clinical isolates of MRSA. A focused library of structural analogs was synthesized to explore initial structure-activity relationships and to identify equipotent myxocoumarin derivatives devoid of the natural nitro substituent to significantly streamline synthetic access. The cytotoxicity of the myxocoumarins as well as their potential to cure bacterial infections in vivo was established using a zebrafish model system. Our results reveal the exceptional antibiotic activity of the myxocoumarin scaffold and hence its potential for the development of novel antibiotics.


Subject(s)
Biological Products , Methicillin-Resistant Staphylococcus aureus , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Microbial Sensitivity Tests , Structure-Activity Relationship , Zebrafish
14.
Eur J Med Chem ; 205: 112533, 2020 Nov 01.
Article in English | MEDLINE | ID: mdl-32739550

ABSTRACT

We have prepared a series of ten 3-arylcoumarin molecules, their respective fac-[Re(CO)3(bpy)L]+ and fac-[Re(CO)3(L⁀L)Br] complexes and tested all compounds for their antimicrobial efficacy. Whereas the 3-arylcoumarin ligands are virtually inactive against the human-associated pathogens with minimum inhibitory concentrations (MICs) > 150 µM, when coordinated to the fac-[Re(CO)3]+ core, most of the resulting complexes showed remarkable antibacterial potency. Several rhenium complexes exhibit activity in nanomolar concentrations against Gram-positive pathogens such as Staphylococcus aureus strains, including methicillin-resistant S. aureus (MRSA) and Enterococcus faecium. The molecules do not affect bacterial cell membrane potential, but some of the most potent complexes strongly interact with DNA, indicating it as a possible target for their mode of action. In vivo studies in the zebrafish model showed that the complexes with anti-staphylococcal/MRSA activity were non-toxic to the organism even at much higher doses of the corresponding MICs. In the zebrafish-MRSA infection model, the complexes increased the survival rate of infected fish up to 100% and markedly reduced bacterial burden. Moreover, all rescued fish developed normally following the treatments with the metallic compounds.


Subject(s)
Coordination Complexes/chemical synthesis , Coordination Complexes/pharmacology , Coumarins/chemical synthesis , Coumarins/pharmacology , Drug Design , Methicillin-Resistant Staphylococcus aureus/drug effects , Rhenium/chemistry , Animals , Chemistry Techniques, Synthetic , Coordination Complexes/chemistry , Coumarins/chemistry , Microbial Sensitivity Tests , Zebrafish
15.
Eur J Med Chem ; 204: 112583, 2020 Oct 15.
Article in English | MEDLINE | ID: mdl-32731186

ABSTRACT

Combination therapy targeting both tumor growth and vascularization is considered to be a cornerstone for colorectal carcinomas (CRC) treatment. However, the major obstacles of most clinical anticancer drugs are their weak selective activity towards cancer cells and inherent inner organs toxicity, accompanied with fast drug resistance development. In our effort to discover novel selective and non-toxic agents effective against CRC, we designed, synthesized and characterized a series of rhenium(I) tricarbonyl-based complexes with increased lipophilicity. Two of these novel compounds were discovered to possess remarkable anticancer, anti-angiogenic and antimetastatic activity in vivo (zebrafish-human HCT-116 xenograft model), being effective at very low doses (1-3 µM). At doses as high as 250 µM the complexes did not provoke toxicity issues encountered in clinical anticancer drugs (cardio-, hepato-, and myelotoxicity). In vivo assays showed that the two compounds exceed the anti-tumor and anti-angiogenic activity of clinical drugs cisplatin and sunitinib malate, and display a large therapeutic window.


Subject(s)
Colorectal Neoplasms/pathology , Coordination Complexes/chemistry , Coordination Complexes/pharmacology , Drug Design , Rhenium/chemistry , Angiogenesis Inhibitors/chemistry , Angiogenesis Inhibitors/pharmacology , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Dose-Response Relationship, Drug , HCT116 Cells , Humans , Neoplasm Metastasis , Xenograft Model Antitumor Assays , Zebrafish
16.
Dalton Trans ; 49(31): 10880-10894, 2020 Aug 11.
Article in English | MEDLINE | ID: mdl-32716429

ABSTRACT

New dinuclear silver(i) complexes with N,N',N'',N'''-tetrakis(2-pyridylmethyl)-1,4,8,11-tetraazacyclotetradecane (tpmc), [Ag2(NO3)(tpmc)]NO3·1.7H2O (1), [Ag2(CF3SO3)2(tpmc)] (2), and [Ag2(tpmc)](BF4)2 (3) were synthesized and characterized by NMR (1H and 13C), IR and UV-Vis spectroscopy, cyclic voltammetry and molar conductivity measurements. The molecular structures of the complexes were determined by single-crystal X-ray diffraction analysis. The spectroscopic and crystallographic data showed that the structure of the complexes strongly depends on the nature of the counteranion of silver(i) salt used for their synthesis. The antimicrobial activity of complexes 1-3 was examined against Gram-positive and Gram-negative bacteria and different species of unicellular fungus Candida spp. The ability of these complexes to inhibit the formation of Candida biofilms and to eradicate the already formed biofilms was tested in the standard microtiter plate-based assay. In addition, a bioelectrochemical testing of the antimicrobial activity of complex 1 against early biofilm was also performed. The obtained results indicated that complexes 1-3 showed increased activity toward Gram-negative bacteria and Candida spp. and could inhibit the formation of biofilms. In most cases, these complexes had positive selectivity indices and showed similar or even better activity with respect to the clinically used silver(i) sulfadiazine (AgSD). The values of the binding constants for complexes 1-3 to bovine serum albumin (BSA) were found to be high enough to indicate their binding to this biomolecule, but not so high as to prevent their release upon arrival at the target site. Moreover, the positive values of partition coefficients for these complexes indicated their ability to be transported through the cell membrane. Once inside the cell, complexes 1-3 could induce the formation of the reactive oxygen species (ROS) in C. albicans cells and/or interact with DNA. Taken together, silver(i) complexes with the tpmc ligand could be considered as novel antimicrobial compounds with favourable pharmacological properties, being safer than AgSD.


Subject(s)
Anti-Infective Agents , Coordination Complexes , Pyridines , Silver , Anti-Infective Agents/chemistry , Anti-Infective Agents/pharmacology , Biofilms/drug effects , Candida albicans/drug effects , Candida albicans/growth & development , Candida albicans/metabolism , Candida albicans/physiology , Coordination Complexes/chemistry , Coordination Complexes/pharmacology , DNA/metabolism , Gram-Negative Bacteria/drug effects , Gram-Negative Bacteria/growth & development , Gram-Negative Bacteria/physiology , Gram-Positive Bacteria/drug effects , Gram-Positive Bacteria/growth & development , Gram-Positive Bacteria/physiology , Ligands , Pyridines/chemistry , Pyridines/pharmacology , Reactive Oxygen Species/metabolism , Serum Albumin, Bovine/metabolism , Silver/chemistry , Silver/pharmacology
17.
Pharmaceutics ; 12(5)2020 May 25.
Article in English | MEDLINE | ID: mdl-32466116

ABSTRACT

Systemic toxicity and severe side effects are commonly associated with anticancer chemotherapies. New strategies based on enhanced drug selectivity and targeted delivery to cancer cells while leaving healthy tissue undamaged can reduce the global patient burden. Herein, we report the design, synthesis and characterization of a bio-inspired hybrid multifunctional drug delivery system based on diatom microalgae. The microalgae's surface was chemically functionalized with hybrid vitamin B12-photoactivatable molecules and the materials further loaded with highly active rhenium(I) tricarbonyl anticancer complexes. The constructs showed enhanced adherence to colorectal cancer (CRC) cells and slow release of the chemotherapeutic drugs. The overall toxicity of the hybrid multifunctional drug delivery system was further enhanced by photoactivation of the microalgae surface. Depending on the construct and anticancer drug, a 2-fold increase in the cytotoxic efficacy of the drug was observed upon light irradiation. The use of this targeted drug delivery strategy, together with selective spatial-temporal light activation, may lead to lower effective concentration of anticancer drugs, thereby reducing medication doses, possible side effects and overall burden for the patient.

18.
Bioinorg Chem Appl ; 2020: 3812050, 2020.
Article in English | MEDLINE | ID: mdl-32351550

ABSTRACT

1,2-Bis(4-pyridyl)ethane (bpa) and 1,2-bis(4-pyridyl)ethene (bpe) were used for the synthesis of polynuclear silver(I) complexes, {[Ag(bpa)]NO3}n (1), {[Ag(bpa)2]CF3SO3 .H2O}n (2) and {[Ag(bpe)]CF3SO3}n (3). In complexes 1-3, the corresponding nitrogen-containing heterocycle acts as a bridging ligand between two Ag(I) ions. In vitro antimicrobial activity of these complexes, along with the ligands used for their synthesis, was evaluated against the broad panel of Gram-positive and Gram-negative bacteria and fungi. The silver(I) complexes 1-3 showed selectivity towards Candida spp. and Gram-negative Escherichia coli in comparison to the other investigated bacterial strains, effectively inhibiting the growth of four different Candida species with minimal inhibitory concentrations (MICs) between 2.5 and 25 µg/mL and the growth of E. coli, with MIC value being 12.5 µg/mL. Importantly, complex 2 significantly reduced C. albicans filamentation, an essential process for its pathogenesis. Antiproliferative effect on the normal human lung fibroblast cell line MRC-5 was also evaluated with the aim of determining the therapeutic potential of the complexes 1-3. The interactions of these complexes with calf thymus DNA (ctDNA) and bovine serum albumin (BSA) were studied to evaluate their binding activities towards these biomolecules for possible insights on their mode of action.

19.
J Inorg Biochem ; 208: 111089, 2020 07.
Article in English | MEDLINE | ID: mdl-32442762

ABSTRACT

Three novel Zn(II) complexes, [ZnCl2(qz)2] (1), [ZnCl2(1,5-naph)]n (2) and [ZnCl2(4,7-phen)2] (3), where qz is quinazoline, 1,5-naph is 1,5-naphthyridine and 4,7-phen is 4,7-phenanthroline, were synthesized by the reactions of ZnCl2 and the corresponding N-heterocyclic ligand in 1:2 molar ratio in ethanol at ambient temperature. The characterization of these complexes was done by NMR, IR and UV-Vis spectroscopy, and their crystal structures were determined by single-crystal X-ray diffraction analysis. Complexes 1 and 3 are mononuclear species, in which Zn(II) ion is tetrahedrally coordinated by two nitrogen atoms belonging to two qz or 4,7-phen ligands, respectively, and by two chloride anions, while complex 2 is a 1D coordination polymer that contains 1,5-naph as bridging ligand between two metal ions. In agar disc-diffusion assay, complexes 1-3 manifested good inhibitory activity against two investigated Candida strains (C. albicans and C. parapsilosis), while not inducing toxic effects on the healthy human fibroblast cell line (MRC-5). This activity was not fungicidal, as revealed by the broth microdilution assay, however complex 3 showed the ability to modulate Candida hyphae formation, which is an important process during infection and showed significant synergistic effect with clinically used antifungal polyene nystatin.


Subject(s)
Antifungal Agents , Candida albicans/growth & development , Candida parapsilosis/growth & development , Coordination Complexes , Heterocyclic Compounds , Nystatin , Zinc , Antifungal Agents/chemical synthesis , Antifungal Agents/chemistry , Antifungal Agents/pharmacology , Cell Line, Tumor , Coordination Complexes/agonists , Coordination Complexes/chemical synthesis , Coordination Complexes/chemistry , Coordination Complexes/pharmacology , Drug Synergism , Heterocyclic Compounds/agonists , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Humans , Nystatin/agonists , Nystatin/chemistry , Nystatin/pharmacology , Zinc/agonists , Zinc/chemistry , Zinc/pharmacology
20.
Dalton Trans ; 49(18): 6084-6096, 2020 May 14.
Article in English | MEDLINE | ID: mdl-32319493

ABSTRACT

Infections of the cow udder leading to mastitis and lower milk quality are one of the biggest problems in the dairy industry worldwide. Unfortunately, therapeutic options for the treatment of cow mastitis are limited as a consequence of the development of pathogens that are resistant to conventionally used antibiotics. In the search for agents that will be active against cow mastitis associated pathogens, in the present study, five new silver(i) complexes with different chelating pyridine-4,5-dicarboxylate types of ligands, [Ag(NO3)(py-2py)]n (1), [Ag(NO3)(py-2metz)]n (2), [Ag(CH3CN)(py-2py)]BF4 (3), [Ag(py-2tz)2]BF4 (4) and [Ag(py-2metz)2]BF4 (5), py-2py is dimethyl 2,2'-bipyridine-4,5-dicarboxylate, py-2metz is dimethyl 2-(4-methylthiazol-2-yl)pyridine-4,5-dicarboxylate and py-2tz is dimethyl 2-(thiazol-2-yl)pyridine-4,5-dicarboxylate, were synthesized, structurally characterized and assessed for in vitro antimicrobial activity using both standard bioassay and clinical isolates from a contaminated milk sample obtained from a cow with mastitis. These complexes showed remarkable activity against the standard panel of microorganisms and a selection of clinical isolates from the milk of the cow diagnosed with mastitis. With the aim of determining the therapeutic potential of silver(i) complexes, their toxicity in vivo against the model organism, Caenorhabditis elegans (C. elegans), was investigated. The complexes that had the best therapeutic profile, 2 and 5, induced bacterial membrane depolarization and the production of reactive oxygen species (ROS) in Candida albicans cells and inhibited the hyphae as well as the biofilm formation. Taken together, the presented data suggest that the silver(i) complexes with pyridine ligands could be considered for the treatment of microbial pathogens, which are causative agents of cow mastitis.


Subject(s)
Antifungal Agents/pharmacology , Caenorhabditis elegans/drug effects , Candida albicans/drug effects , Coordination Complexes/pharmacology , Mastitis/drug therapy , Pyridines/chemistry , Silver/pharmacology , Animals , Antifungal Agents/chemical synthesis , Antifungal Agents/chemistry , Caenorhabditis elegans/pathogenicity , Candida albicans/growth & development , Candida albicans/metabolism , Cattle , Coordination Complexes/chemical synthesis , Coordination Complexes/chemistry , Crystallography, X-Ray , Female , Ligands , Mastitis/microbiology , Microbial Sensitivity Tests , Models, Molecular , Molecular Structure , Particle Size , Reactive Oxygen Species/metabolism , Silver/chemistry , Surface Properties
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