A series of 1,3,5-triazinyl aminobenzenesulfonamides substituted by aminoalcohol, aminostilbene, and aminochalcone structural motifs was synthesized as potential human carbonic anhydrase (hCA) inhibitors. The compounds were evaluated on their inhibition of tumor-associated hCA IX and hCA XII, hCA VII isoenzyme present in the brain, and physiologically important hCA I and hCA II. While the test compounds had only a negligible effect on physiologically important isoenzymes, many of the studied compounds significantly affected the hCA IX isoenzyme. Several compounds showed activity against hCA XII; (E)-4-{2-[(4-[(2,3-dihydroxypropyl)amino]-6-[(4-styrylphenyl)amino]-1,3,5-triazin-2-yl)amino]ethyl}benzenesulfonamide (31) and (E)-4-{2-[(4-[(4-hydroxyphenyl)amino]-6-[(4-styrylphenyl)amino]-1,3,5-triazin-2-yl)amino]ethyl}benzenesulfonamide (32) were the most effective inhibitors with KIs = 4.4 and 5.9 nM, respectively. In addition, the compounds were tested against vancomycin-resistant Enterococcus faecalis (VRE) isolates. (E)-4-[2-({4-[(4-cinnamoylphenyl)amino]-6-[(4-hydroxyphenyl)amino]-1,3,5-triazin-2-yl}amino)ethyl]benzenesulfonamide (21) (MIC = 26.33 μM) and derivative 32 (MIC range 13.80-55.20 μM) demonstrated the highest activity against all tested strains. The most active compounds were evaluated for their cytotoxicity against the Human Colorectal Tumor Cell Line (HCT116 p53 +/+). Only 4,4'-[(6-chloro-1,3,5-triazin-2,4-diyl)bis(iminomethylene)]dibenzenesulfonamide (7) and compound 32 demonstrated an IC50 of ca. 6.5 μM; otherwise, the other selected derivatives did not show toxicity at concentrations up to 50 μM. The molecular modeling and docking of active compounds into various hCA isoenzymes, including bacterial carbonic anhydrase, specifically α-CA present in VRE, was performed to try to outline a possible mechanism of selective anti-VRE activity.
- MeSH
- antibakteriální látky farmakologie MeSH
- antitumorózní látky farmakologie terapeutické užití MeSH
- enterokoky rezistentní vůči vankomycinu účinky léků MeSH
- HCT116 buňky MeSH
- inhibitory karboanhydras farmakologie MeSH
- karboanhydrasa I antagonisté a inhibitory MeSH
- karboanhydrasa II antagonisté a inhibitory MeSH
- karboanhydrasa IX antagonisté a inhibitory MeSH
- karboanhydrasy účinky léků MeSH
- lidé MeSH
- nádory farmakoterapie MeSH
- simulace molekulární dynamiky MeSH
- simulace molekulového dockingu MeSH
- sulfonamidy farmakologie MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- bakteriální léková rezistence genetika imunologie MeSH
- Enterococcus faecalis genetika účinky léků MeSH
- Enterococcus faecium genetika účinky léků MeSH
- enterokoky rezistentní vůči vankomycinu * genetika patogenita účinky léků MeSH
- fenotyp MeSH
- genotyp MeSH
- glykopeptidy farmakologie metabolismus terapeutické užití MeSH
- infekce spojené se zdravotní péčí mikrobiologie prevence a kontrola MeSH
- lidé MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
The most prevalent type of acquired vancomycin resistance in Enterococcus faecium (VREfm) is encoded by the vanA transposon Tn1546, mainly located on transferable plasmids. vanA plasmids have been characterized in VREfm from a variety of sources but not wild birds. The aim of this study was to analyse the genetic context of VREfm strains recovered from wild corvid birds and to compare their plasmid and strain characteristics with human strains. To achieve that, 75 VREfm isolates, including strains from wild birds recovered during wide surveillance studies performed in Europe, Canada and the United States (2010-2013), and clinical and wastewater strains from Czech Republic, a region lacking data about vanA plasmids, were analysed. Their population structure, presence of major putative virulence markers and characterization of vanA transposons and plasmids were established. VREfm from wild birds were mainly associated with major human lineages (ST18 and ST78) circulating in hospitals worldwide and were enriched in putative virulence markers that are highly associated with clinical E. faecium from human infections. They also carried plasmids of the same families usually found in the clinical setting [RCR, small theta plasmids, RepA_N (pRUM/pLG1) and Inc18]. The clinically widespread IS1251-carrying Tn1546 type "F" was predominant and Tn1546-vanA was mainly located on pRUM/Axe-Txe (USA) and Inc18- or pLG1-like (Europe) plasmids. VREfm from hospitals and wastewaters carried Tn1546-vanA in different plasmid types including mosaic pRUM-Inc18 plasmids, not identified in wild birds. This is the first characterization of vanA plasmids obtained from wild birds. A similar plasmid pool seems to exist in different clonal E. faecium backgrounds of humans and wild birds. The isolation of VREfm strains from wild birds that belong to human E. faecium adapted lineages and carry virulence genes, Tn1546 and plasmid variants widespread in the clinical setting is of concern and highlight their role as potential drivers of the global dissemination of vancomycin resistance.
- MeSH
- Enterococcus faecium * účinky léků genetika MeSH
- enterokoky rezistentní vůči vankomycinu * účinky léků genetika MeSH
- grampozitivní bakteriální infekce mikrobiologie přenos veterinární MeSH
- lidé MeSH
- Passeriformes mikrobiologie MeSH
- plazmidy genetika MeSH
- rezistence na vankomycin genetika MeSH
- zoonózy mikrobiologie přenos MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
A series of 13 salicylamide derivatives was assessed for antibacterial activity against three isolates of vancomycin-resistant Enterococcus faecalis (VRE) and Enterococcus faecalis ATCC 29212 as a quality standard. The minimum inhibitory concentration was determined by the broth microdilution method with subsequent subcultivation of aliquots to assess minimum bactericidal concentration. The growth kinetics was established by the time-kill assay. Ampicillin, ciprofloxacin, tetracycline and vancomycin were used as the reference antibacterial drugs. Three of the investigated compounds showed strong bacteriostatic activity against VRE (0.199-25 µM) comparable to or more potent than ampicillin and ciprofloxacin. In addition, these compounds were tested for synergistic effect with vancomycin, ciprofloxacin and tetracycline, while 5-chloro-2-hydroxy-N-[4-(trifluoromethyl)phenyl]benzamide showed the highest potency as well as synergistic activity with vancomycin against VRE 368. Screening of the cytotoxicity of the most effective compounds was performed using human monocytic leukemia THP-1 cells, and based on LD50 values, it can be stated that the compounds have insignificant toxicity against human cells.
- MeSH
- antibakteriální látky chemie farmakologie MeSH
- Enterococcus faecalis účinky léků MeSH
- enterokoky rezistentní vůči vankomycinu účinky léků MeSH
- lidé MeSH
- mikrobiální testy citlivosti MeSH
- molekulární struktura MeSH
- nádorové buněčné linie MeSH
- vankomycin chemie farmakologie MeSH
- viabilita buněk účinky léků MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The present study was performed to evaluate the antibacterial activities of an antimicrobial peptide (CSpK14) and the synergies thereof with β-lactams against vancomycin-resistant Staphylococcus aureus (VRSA) and Enterococci (VRE). Our strain was isolated from fermented food (kimchi), which is 99.79 % homologous with Bacillus amyloliquefaciens subsp. plantarum FZB42(T). CSpK14 was purified to homogeneity by diammonium sulfate precipitation, concentration, dialysis, and followed by two-stage chromatographic separation, i.e., Sepharose Cl-6B and Sephadex G-25 chromatography, and had a molar mass of ~4.6 kDa via Tricine SDS-PAGE and in situ examination. It was stable at pH 6.0-11.5 and temperature up to 80 °C. In addition, it was also stable with various metal ions, solvents, and proteases. The N-terminal amino acid sequence was H-Y-D-P-G-D-D-S-G-N-T-G and did not show any significant homology with reported peptides. However, it shows some degrees of identity with alpha-2-macroglobulin and ligand-gated channel protein from different microorganisms. CSpK14 significantly reduced the minimum inhibitory concentrations (MICs) of β-lactams and had no effect on non-β-lactams against VRSA and VRE. MICs of CSpK14/oxacillin and CSpK14/ampicillin were reduced by 8- to 64-fold and 2- to 16-fold, respectively. The time killing assay between CSpK14/oxacillin (2.29-2.37 Δlog10CFU/mL at 24 h) and CSpK14/ampicillin (2.30-2.38 Δlog10CFU/mL at 24 h) being >2-fold and fractional inhibitory concentration index ˂0.5 revealed synergy. Furthermore, the biofilms formed by VRSA and VRE were reduced completely. CSpK14 was simple to purify, had low molecular mass, was stable over a wide pH range or tested chemicals, had broad inhibitory spectrum, and possessed potent synergistic antimicrobial-antibiofilm properties. CSpK14 synergistically enhanced the efficacy of β-lactams and is therefore suitable for combination therapy.
- MeSH
- ampicilin farmakologie MeSH
- antibakteriální látky biosyntéza izolace a purifikace farmakologie MeSH
- Bacillus amyloliquefaciens klasifikace imunologie metabolismus MeSH
- biofilmy účinky léků růst a vývoj MeSH
- chromatografie iontoměničová MeSH
- enterokoky rezistentní vůči vankomycinu účinky léků růst a vývoj MeSH
- fylogeneze MeSH
- kationické antimikrobiální peptidy biosyntéza izolace a purifikace farmakologie MeSH
- kombinovaná farmakoterapie MeSH
- mikrobiální testy citlivosti MeSH
- oxacilin farmakologie MeSH
- rezistence na vankomycin účinky léků MeSH
- sekvence aminokyselin MeSH
- stabilita proteinů MeSH
- Staphylococcus aureus účinky léků růst a vývoj MeSH
- synergismus léků MeSH
- Publikační typ
- časopisecké články MeSH
- Klíčová slova
- avoparcin,
- MeSH
- bakteriální léková rezistence genetika účinky léků MeSH
- Enterococcus fyziologie genetika klasifikace ultrastruktura MeSH
- enterokoky rezistentní vůči vankomycinu * genetika účinky léků ultrastruktura MeSH
- exprese genu genetika účinky léků MeSH
- glykopeptidy účinky léků MeSH
- infekce spojené se zdravotní péčí mortalita přenos MeSH
- lidé MeSH
- vankomycin MeSH
- zoonózy přenos MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
