4-aminobenzoic acid (PABA), an essential nutrient for many human pathogens, but dispensable for humans, and its derivatives have exhibited various biological activities. In this study, we combined two pharmacophores using a molecular hybridization approach: this vitamin-like molecule and various aromatic aldehydes, including salicylaldehydes and 5-nitrofurfural, via imine bond in one-step reaction. Resulting Schiff bases were screened as potential antimicrobial and cytotoxic agents. The simple chemical modification of non-toxic PABA resulted in constitution of antibacterial activity including inhibition of methicillin-resistant Staphylococcus aureus (minimum inhibitory concentrations, MIC, from 15.62 µM), moderate antimycobacterial activity (MIC ≥ 62.5 µM) and potent broad-spectrum antifungal properties (MIC of ≥ 7.81 µM). Some of the Schiff bases also exhibited notable cytotoxicity for cancer HepG2 cell line (IC50 ≥ 15.0 µM). Regarding aldehyde used for the derivatization of PABA, it is possible to tune up the particular activities and obtain derivatives with promising bioactivities.
- MeSH
- antibakteriální látky chemie farmakologie MeSH
- buňky Hep G2 MeSH
- cytotoxiny chemie farmakologie MeSH
- kyselina 4-aminobenzoová chemie farmakologie MeSH
- kyselina listová chemie farmakologie MeSH
- lidé MeSH
- methicilin rezistentní Staphylococcus aureus účinky léků růst a vývoj MeSH
- mikrobiální testy citlivosti MeSH
- viabilita buněk účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
A series of twenty-six methoxylated and methylated N-aryl-1-hydroxynaphthalene- 2-carboxanilides was prepared and characterized as potential anti-invasive agents. The molecular structure of N-(2,5-dimethylphenyl)-1-hydroxynaphthalene-2-carboxamide as a model compound was determined by single-crystal X-ray diffraction. All the analysed compounds were tested against the reference strain Staphylococcus aureus and three clinical isolates of methicillin-resistant S.aureus as well as against Mycobacterium tuberculosis and M. kansasii. In addition, the inhibitory profile of photosynthetic electron transport in spinach (Spinacia oleracea L.) chloroplasts was specified. In vitro cytotoxicity of the most effective compounds was tested on the human monocytic leukaemia THP-1 cell line. The activities of N-(3,5-dimethylphenyl)-, N-(3-fluoro-5-methoxy-phenyl)- and N-(3,5-dimethoxyphenyl)-1-hydroxynaphthalene-2-carbox- amide were comparable with or even better than the commonly used standards ampicillin and isoniazid. All promising compounds did not show any cytotoxic effect at the concentration >30 µM. Moreover, an in silico evaluation of clogP features was performed for the entire set of the carboxamides using a range of software lipophilicity predictors, and cross-comparison with the experimentally determined lipophilicity (log k), in consensus lipophilicity estimation, was conducted as well. Principal component analysis was employed to illustrate noticeable variations with respect to the molecular lipophilicity (theoretical/experimental) and rule-of-five violations. Additionally, ligand-oriented studies for the assessment of the three-dimensional quantitative structure-activity relationship profile were carried out with the comparative molecular surface analysis to determine electron and/or steric factors that potentially contribute to the biological activities of the investigated compounds.
- MeSH
- ampicilin farmakologie MeSH
- analýza hlavních komponent MeSH
- anilidy chemická syntéza chemie farmakologie MeSH
- antibakteriální látky chemická syntéza chemie farmakologie MeSH
- chloroplasty účinky léků fyziologie MeSH
- fotosyntéza účinky léků MeSH
- isoniazid farmakologie MeSH
- lidé MeSH
- methicilin rezistentní Staphylococcus aureus účinky léků růst a vývoj MeSH
- metylace MeSH
- mikrobiální testy citlivosti MeSH
- Mycobacterium kansasii účinky léků růst a vývoj MeSH
- Mycobacterium tuberculosis účinky léků růst a vývoj MeSH
- naftoly chemická syntéza chemie farmakologie MeSH
- Spinacia oleracea chemie účinky léků metabolismus MeSH
- THP-1 buňky MeSH
- transport elektronů účinky léků MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- srovnávací studie MeSH
Staphylococcus aureus may be a highly virulent human pathogen, especially when it is able to form a biofilm, and it is resistant to antibiotic. Infections caused by these bacteria significantly affect morbidity and mortality, primarily in hospitalized patients. Treatment becomes more expensive, more toxic, and prolonged. This is the reason why research on alternative therapies should be one of the main priorities of medicine and biotechnology. A promising alternative treatment approach is bacteriophage therapy. The effect of the anti-staphylococcal bacteriophage preparation Stafal® on biofilm reduction was assessed on nine S. aureus strains using both sonication with subsequent quantification of surviving cells on the catheter surface and evaluation of biofilm reduction in microtiter plates. It was demonstrated that the bacteriophages destroy planktonic cells very effectively. However, to destroy cells embedded in the biofilm effectively requires a concentration at least ten times higher than that provided by the commercial preparation. The catheter disc method (CDM) allowed easier comparison of the effect on planktonic cells and cells in a biofilm than the microtiter plate (MTP) method.
- MeSH
- antiinfekční látky * MeSH
- bakteriologické techniky MeSH
- biofilmy * MeSH
- lidé MeSH
- methicilin rezistentní Staphylococcus aureus růst a vývoj izolace a purifikace virologie MeSH
- mikrobiální viabilita MeSH
- počet mikrobiálních kolonií MeSH
- stafylokokové bakteriofágy fyziologie MeSH
- stafylokokové infekce mikrobiologie MeSH
- Staphylococcus aureus růst a vývoj izolace a purifikace virologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
PURPOSE: Antibiotic-loaded polymethylmethacrylate-based bone cement has been implemented in orthopaedics to cope with implant-related infections associated with the formation of bacterial biofilms. In the context of emerging bacterial resistance to current antibiotics, we examined the efficacy of short antimicrobial peptide-loaded bone cement in inhibiting bacterial adhesion and consequent biofilm formation on its surface. METHODOLOGY: The ability of α-helical antimicrobial peptides composed of 12 amino acid residues to prevent bacterial biofilm [methicillin-resistant Staphylococcus aureus (MRSA), Staphylococcus epidermidis, Pseudomonas aeruginosa and Escherichia coli] formation on the surface of model implants made from polymethylmethacrylate-based bone cement was evaluated by colony-forming unit (c.f.u.) counting of bacteria released by sonication from the biofilms formed on their surfaces. The biofilms on model implant surfaces were also visualized by light microscopy after staining with tetrazolium dye (MTT) and by scanning electron microscopy. RESULTS: When incorporated in the implants, these peptides caused a mean reduction in the number of bacterial cells attached to implants' surfaces (by five orders of magnitude), and 88 % of these implants showed no bacterial adhesion after being exposed to growth media containing various bacteria. CONCLUSION: The results showed that the antibiofilm activity of these peptides was comparable to that of the antibiotics, but the peptides exhibited broader specificity than the antibiotics. Given the rapid development of antibiotic resistance, antimicrobial peptides show promise as a substitute for antibiotics for loading into bone cements.
- MeSH
- antibakteriální látky farmakologie MeSH
- antiinfekční látky farmakologie MeSH
- bakteriální adheze účinky léků MeSH
- biofilmy účinky léků růst a vývoj MeSH
- kostní cementy MeSH
- methicilin rezistentní Staphylococcus aureus účinky léků růst a vývoj MeSH
- mikrobiální testy citlivosti MeSH
- peptidy chemická syntéza farmakologie MeSH
- polymethylmethakrylát MeSH
- protézy a implantáty mikrobiologie MeSH
- Pseudomonas aeruginosa účinky léků růst a vývoj MeSH
- Staphylococcus epidermidis účinky léků růst a vývoj MeSH
- Publikační typ
- časopisecké články MeSH
Staphylococcal infections are often hard to treat due to increasing resistance, especially to β-lactams. Previous studies described the synergy between common antibiotics and isoflavonoids; however, little is yet known about the combinatory effects of antibiotics with products of human isoflavone metabolism. In this study, demethyltexasin (DT), a human body metabolite of soybean isoflavones, was evaluated for its possible antistaphylococcal combinatory effect with amoxicillin and oxacillin. For comparison, common therapeutically used combination of amoxicillin/clavulanic acid was tested. DT showed strong synergistic interactions against most of Staphylococcus aureus strains when combined with amoxicillin (sum of fractional inhibitory concentrations [ΣFIC] 0.257-0.461) and oxacillin (ΣFIC 0.109-0.484). When oxacillin was combined with DT, resistance to this antibiotic was overcome in many cases. Moreover, antibiotic/DT combinations were effective mainly against methicillin-resistant S. aureus (MRSA); however, the commonly used drug amoxicillin/clavulanic acid was effective only against sensitive strains. Our results indicated DT as a compound able to act synergistically with β-lactams. In addition, some combinations are effective against MRSA and decrease staphylococcal resistance. To the best of our knowledge this is the first report of the antimicrobial synergistic effects of isoflavone human body metabolite with common antibiotics. DT seems to be a possible candidate for further research focused on antistaphylococcal drug development, especially against antibiotic-resistant strains.
- MeSH
- amoxicilin farmakologie MeSH
- antibakteriální látky farmakologie MeSH
- fixní kombinace léků MeSH
- isoflavony farmakologie MeSH
- kombinace amoxicilinu a kyseliny klavulanové farmakologie MeSH
- lidé MeSH
- methicilin rezistentní Staphylococcus aureus účinky léků růst a vývoj MeSH
- mikrobiální testy citlivosti MeSH
- oxacilin farmakologie MeSH
- rezistence na methicilin účinky léků MeSH
- Staphylococcus aureus účinky léků růst a vývoj MeSH
- synergismus léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Series of thirteen 1-[(2-chlorophenyl)carbamoyl]naphthalen-2-yl carbamates and thirteen 1-[(2-nitrophenyl)carbamoyl]naphthalen-2-yl carbamates with alkyl/cycloalkyl/arylalkyl chains were prepared and characterized. Primary in vitro screening of the synthesized compounds was performed against Staphylococcus aureus, two methicillin-resistant S. aureus strains, Mycobacterium marinum, and M. kansasii. 1-[(2-Chlorophenyl)carbamoyl]naphthalen-2-yl ethylcarbamate and 1-[(2-nitrophenyl)carbamoyl]naphthalen-2-yl ethylcarbamate showed antistaphylococcal (MICs = 42 µM against MRSA) and antimycobacterial (MICs = 21 µM) activity against the tested strains comparable with or higher than that of the standards ampicillin and isoniazid. In the case of bulkier carbamate tails (R > propyl/isopropyl), the activity was similar (MICs ca. 70 µM). Screening of the cytotoxicity of both of the most effective compounds was performed using THP-1 cells, and no significant lethal effect was observed (LD50 >30 µM). The structure-activity relationships are discussed.
- MeSH
- antiinfekční látky * chemická syntéza chemie farmakologie MeSH
- cytotoxiny * chemická syntéza chemie farmakologie MeSH
- karbamáty * chemická syntéza chemie farmakologie MeSH
- lidé MeSH
- methicilin rezistentní Staphylococcus aureus růst a vývoj MeSH
- Mycobacterium tuberculosis růst a vývoj MeSH
- nádorové buněčné linie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Context C-6-Geranylated flavonoids possess promising biological activities. These substances could be a source of lead compounds for the development of therapeutics. Objective The study was designed to evaluate their antibacterial and antileishmanial activity. Materials and methods C-6-Geranylated flavanones were tested in micromolar concentrations against promastigote forms of Leishmania brazilensis, L. donovani, L. infantum, and L. panamensis against methicillin-resistant Staphylococcus aureus (MRSA); and synergistic potential with antibiotics was analyzed. IC50 values (after 72 h) were calculated and compared with that of miltefosine. Flow cytometry and DNA fragmentation analysis were used the mechanism of the effect. Geranylated flavanones or epigallocatechin gallate were combined with oxacillin, tetracycline, and ciprofloxacin, and the effects of these two-component combinations were evaluated. Minimal inhibitory concentrations (MICs) and minimal bactericidal concentrations (MBCs) were established (after 24 h), the synergy was measured by the checkerboard titration technique, and the sums of the fractional inhibitory concentrations (∑FICs) were computed. Results 3'-O-Methyl-5'-O-methyldiplacone and 3'-O-methyldiplacone showed good antileishmanial activities (IC50 8-42 μM). 3'-O-Methyl-5'-hydroxydiplacone activates the apoptotic death at leishmanias, the effect of 3'-O-methyl-5'-O-methyldiplacone has another mechanism. The test of the antibacterial activity showed good effects of 3'-O-methyldiplacol and mimulone against MRSA (MIC 2-16 μg/mL), and in six cases, the results showed synergistic effects when combined with oxacillin. Synergistic effects were also found for the combination of epigallocatechin gallate with tetracycline or oxacillin. Conclusion This work demonstrates anti-MRSA and antileishmanial potential of geranylated flavanones and uncovers their promising synergistic activities with antibiotics. In addition, the mechanism of antileishmanial effect is proposed.
- MeSH
- antibakteriální látky izolace a purifikace farmakologie MeSH
- antiparazitární látky izolace a purifikace farmakologie MeSH
- apoptóza účinky léků MeSH
- časové faktory MeSH
- flavonoidy izolace a purifikace farmakologie MeSH
- fytoterapie MeSH
- léčivé rostliny MeSH
- Leishmania účinky léků růst a vývoj MeSH
- Magnoliopsida * chemie MeSH
- methicilin rezistentní Staphylococcus aureus účinky léků růst a vývoj MeSH
- mikrobiální testy citlivosti MeSH
- ovoce MeSH
- prenylace MeSH
- rostlinné extrakty izolace a purifikace farmakologie MeSH
- synergismus léků MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- Publikační typ
- časopisecké články MeSH
- srovnávací studie MeSH
- MeSH
- amputace ošetřování MeSH
- antibakteriální látky terapeutické užití MeSH
- antiinfekční látky lokální MeSH
- chronická nemoc terapie MeSH
- diabetická noha * farmakoterapie chirurgie terapie MeSH
- dospělí MeSH
- hojení ran MeSH
- hospitalizace MeSH
- instilace léků MeSH
- klostridiové infekce farmakoterapie MeSH
- lidé MeSH
- methicilin rezistentní Staphylococcus aureus růst a vývoj MeSH
- mnohočetná bakteriální léková rezistence * MeSH
- nanočástice terapeutické užití MeSH
- okluzivní ošetření rány MeSH
- onemocnění periferních arterií farmakoterapie MeSH
- prsty nohy chirurgie MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- stříbro terapeutické užití MeSH
- terapie ran pomocí řízeného podtlaku * MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
A series of fifteen new N-alkoxyphenylanilides of 3-hydroxynaphthalene-2-carboxylic acid was prepared and characterized. Primary in vitro screening of the synthesized compounds was performed against Staphylococcus aureus, three methicillin-resistant S. aureus strains, Mycobacterium tuberculosis H37Ra and M. avium subsp. paratuberculosis. Some of the tested compounds showed antibacterial and antimycobacterial activity against the tested strains comparable with or higher than that of the standards ampicillin or rifampicin. 3-Hydroxy-N-(2-propoxyphenyl)naphthalene-2-carboxamide and N-[2-(but-2-yloxy)-phenyl]-3-hydroxynaphthalene-2-carboxamide had MIC = 12 µM against all methicillin-resistant S. aureus strains; thus their activity is 4-fold higher than that of ampicillin. The second mentioned compound as well as 3-hydroxy-N-[3-(prop-2-yloxy)phenyl]-naphthalene-2-carboxamide had MICs = 23 µM and 24 µM against M. tuberculosis respectively. N-[2-(But-2-yloxy)phenyl]-3-hydroxynaphthalene-2-carboxamide demonstrated higher activity against M. avium subsp. paratuberculosis than rifampicin. Screening of the cytotoxicity of the most effective antimycobacterial compounds was performed using THP-1 cells, and no significant lethal effect was observed for the most potent compounds. The compounds were additionally tested for their activity related to inhibition of photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts. N-(3-Ethoxyphenyl)-3-hydroxynaphthalene-2-carboxamide (IC50 = 4.5 µM) was the most active PET inhibitor. The structure-activity relationships are discussed.
- MeSH
- ampicilin farmakologie MeSH
- anilidy chemická syntéza farmakologie MeSH
- antibakteriální látky chemická syntéza farmakologie MeSH
- buněčné linie MeSH
- chloroplasty účinky léků fyziologie MeSH
- fotosyntéza účinky léků fyziologie MeSH
- lidé MeSH
- methicilin rezistentní Staphylococcus aureus účinky léků růst a vývoj MeSH
- mikrobiální testy citlivosti MeSH
- mikrobiální viabilita účinky léků MeSH
- monocyty cytologie účinky léků MeSH
- Mycobacterium avium subsp. paratuberculosis účinky léků růst a vývoj MeSH
- Mycobacterium tuberculosis účinky léků růst a vývoj MeSH
- naftaleny chemická syntéza farmakologie MeSH
- rifampin farmakologie MeSH
- Spinacia oleracea účinky léků fyziologie MeSH
- transport elektronů účinky léků fyziologie MeSH
- viabilita buněk účinky léků MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
A series of nine substituted 2-hydroxy-N-[1-oxo-1-(phenylamino)alkan-2-yl]benzamides was assessed as prospective bactericidal agents against three clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) and S. aureus ATCC 29213 as the reference and quality control strain. The minimum bactericidal concentration was determined by subculturing aliquots from MIC determination onto substance-free agar plates. The bactericidal kinetics of compounds 5-chloro-2-hydroxy-N-[(2S)-3-methyl-1-oxo-1-{[4-(trifluoromethyl)phenyl]amino}butan-2-yl]benzamide (1f), N-{(2S)-1-[(4-bromophenyl)amino]-3-methyl-1-oxobutan-2-yl}-4-chloro-2-hydroxybenzamide (1g), and 4-chloro-N-{(2S)-1-[(3,4-dichlorophenyl)amino]-3-methyl-1-oxobutan-2-yl}-2-hydroxybenzamide (1h) was established by time-kill assay with a final concentration of the compound equal to 1x, 2x, and 4x MIC; aliquots were removed at 0, 4, 6, 8, and 24 h time points. The most potent bactericidal agent was compound 1f exhibiting remarkable rapid concentration-dependent bactericidal effect even at 2x MIC at 4, 6, and 8 h (with a reduction in bacterial count ranging from 3.08 to 3.75 log10 CFU/mL) and at 4x MIC at 4, 6, 8, and 24 h (5.30 log10 CFU/mL reduction in bacterial count) after incubation against MRSA 63718. Reliable bactericidal effect against other strains was maintained at 4x MIC at 24 h.
