Phenylpiperazine 5,5-Dimethylhydantoin Derivatives as First Synthetic Inhibitors of Msr(A) Efflux Pump in Staphylococcus epidermidis

Witek, Karolina; Latacz, Gniewomir; Kaczor, Aneta; Czekajewska, Joanna; Żesławska, Ewa; Chudzik, Anna; Karczewska, E; Nitek, Wojciech; Kieć‐Kononowicz, Katarzyna; Handzlik, Jadwiga

doi:10.3390/molecules25173788

Cited by 8 publications

(8 citation statements)

References 29 publications

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“…Finally, the specific activity (SA) of the selected plant extracts on the accumulation of EtBr by S. aureus USA300 was calculated using the following equation: SA = RFI/ n (µmol), where n is the amount of the selected compound used in this assay. The experiment was repeated three independent times ( Witek et al , 2020 ).…”

Section: Methodsmentioning

confidence: 99%

Evaluation of efflux pump inhibitory activity of some plant extracts and using them as adjuvants to potentiate the inhibitory activity of some antibiotics against Staphylococcus aureus

Alsallami¹,

Alsultan²,

Abbas³

et al. 2023

Open Vet J

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Background: Antibiotic resistant pathogens became a real global threat for human and animal health. This needs to concentrate the efforts to minimise and control these organisms. Efflux pumps are considered as one of the important strategies used by bacteria to exclude the harm materials out of the cell. Inhibition of these pumps can be an active strategy against multidrug resistance (MDR) pathogens. There are two source of efflux pump inhibitors can be used, chemical and natural inhibitors. The chemical origin efflux pump inhibitors have many toxic side effects while the natural origin characterized by a wide margin of safety for the host cell. Aim: In this study the ability of some plant extracts like (propolis show rosemary, clove, capsaicin and cumin) to potentiate the inhibitory activity of some antibiotics as (ciprofloxacin, erythromycin, gentamycin, tetracycline and ampicillin) against S. aureus pathogen were tested. Methods: Efflux pump inhibitory activity of the selected plant extracts were tested using ethidium bromide accumulation assay. Results: The results have shown that Propolis has a significant synergistic effect in combination with ciprofloxacin, erythromycin and gentamycin. While, it has no effect with tetracycline or ampicillin. Also, no synergic effect was noticed in combination of the MIC for the selected plant extracts (rosemary, clove, capsaicin and cumin) with any of the tested antibiotics. Interestingly, according to the results of EtBr accumulation assay, Propolis has potent inhibitory activity against S. aureus (MRS usa300) pump system. Conclusion: This study suggests that Propolis might act as a resistance breaker that is able to restore the activity of ciprofloxacin, erythromycin and gentamycin against S. aureus strains, in case of the Efflux-mediated antimicrobial resistance mechanisms.

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Section: Methodsmentioning

confidence: 99%

Evaluation of efflux pump inhibitory activity of some plant extracts and using them as adjuvants to potentiate the inhibitory activity of some antibiotics against Staphylococcus aureus

Alsallami¹,

Alsultan²,

Abbas³

et al. 2023

Open Vet J

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“…Syntheses of compounds 1-15 (Table 1) were performed according to Scheme 1. Syntheses of compounds 7-9, 15, 16 and 18-20 were published before [48,50]. Syntheses of obtained compounds consisted of (i) N3-alkylation, (ii) N1-alkylation, and (iii or iv) arylpiperazine N-alkylation with suitable alkylation agents (17)(18)(19)(20).…”

Section: Chemistrymentioning

confidence: 99%

The Subtype Selectivity in Search of Potent Hypotensive Agents among 5,5-Dimethylhydantoin Derived α1-Adrenoceptors Antagonists

Kaczor,

Knutelska,

Kucwaj-Brysz

et al. 2023

IJMS

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In order to find new hypotensive drugs possessing higher activity and better selectivity, a new series of fifteen 5,5-dimethylhydantoin derivatives (1–15) was designed. Three-step syntheses, consisting of N-alkylations using standard procedures as well as microwaves, were carried out. Crystal structures were determined for compounds 7–9. All of the synthesized 5,5-dimethylhydantoins were tested for their affinity to α1-adrenergic receptors (α1-AR) using both in vitro and in silico methods. Most of them displayed higher affinity (Ki < 127.9 nM) to α1-adrenoceptor than urapidil in radioligand binding assay. Docking to two subtypes of adrenergic receptors, α1A and α1B, was conducted. Selected compounds were tested for their activity towards two α1-AR subtypes. All of them showed intrinsic antagonistic activity. Moreover, for two compounds (1 and 5), which possess o-methoxyphenylpiperazine fragments, strong activity (IC50 < 100 nM) was observed. Some representatives (3 and 5), which contain alkyl linker, proved selectivity towards α1A-AR, while two compounds with 2-hydroxypropyl linker (11 and 13) to α1B-AR. Finally, hypotensive activity was examined in rats. The most active compound (5) proved not only a lower effective dose than urapidil but also a stronger effect than prazosin.

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“…Several natural or synthetic compounds have been characterized as efflux pump inhibitors (EPIs), including alkamides [8], terpenoids [9], flavonoids [10,11], chalcones [12][13][14], imidazolidines [15], 1,8-naphthyridines sulfonamides [16], 2-phenylquinoline derivatives [17], pyridine-3-boronic acid derivatives [18], and indole-based derivatives [19], among others. Clinically approved drugs for other clinical indications, such as nilotinib and azelastine, have shown good inhibitory activity against NorA [20].…”

Section: Introductionmentioning

confidence: 99%

Modulatory Effect of Croton heliotropiifolius Kunth Ethanolic Extract on Norfloxacin Resistance in Staphylococcus aureus

Brito,

Alcântara,

Leal

et al. 2023

DDC

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The high frequency of infectious diseases has spurred research into effective tactics to combat microorganisms that are resistant to several drugs. The overproduction of the transmembrane efflux pump protein NorA, which may export hydrophilic fluoroquinolones, is a common mechanism of resistance in S. aureus strains. This work evaluated the antimicrobial activity of the ethanolic extract from the leaves of Croton heliotropiifolius (EECH) against different bacterial and fungal strains, as well as investigating its modulating effect on the resistance to norfloxacin in a Staphylococcus aureus SA1199B overproducing the NorA efflux pump. Microdilution assays were used to assess the EECH’s antibacterial efficacy. The MIC of norfloxacin or ethidium bromide (EtBr) against the SA1199B strain was determined in the presence or absence of the EECH in order to assess the modifying influence on drug resistance. The EECH showed no activity against the Gram-positive and Gram-negative bacterial strains tested. The EECH also showed no antifungal activity against Candida albicans ATCC 10231. On the other hand, the extract reduced the MIC values for norfloxacin against SA1199B at subinhibitory concentrations. In addition, the EECH also reduced the MIC values of EtBr at subinhibitory concentrations, suggesting the occurrence of phytochemicals that inhibit efflux pumps. Molecular docking showed that retusin, a flavonoid found in the extract, could compete with norfloxacin at the orthosteric site of the NorA, indicating that it could be a potential efflux pump inhibitor. However, isolated retusin did not enhance the activity of norfloxacin or EtBr and it did not inhibit the EtBr efflux, showing that it is not a NorA inhibitor. Even though C. heliotropiifolius is a source of phytochemicals that function as adjuvants for norfloxacin, isolated retusin cannot be used in conjunction with norfloxacin to treat infections brought on by S. aureus that overproduces NorA.

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Phenylpiperazine 5,5-Dimethylhydantoin Derivatives as First Synthetic Inhibitors of Msr(A) Efflux Pump in Staphylococcus epidermidis

Cited by 8 publications

References 29 publications

Evaluation of efflux pump inhibitory activity of some plant extracts and using them as adjuvants to potentiate the inhibitory activity of some antibiotics against Staphylococcus aureus

Evaluation of efflux pump inhibitory activity of some plant extracts and using them as adjuvants to potentiate the inhibitory activity of some antibiotics against Staphylococcus aureus

The Subtype Selectivity in Search of Potent Hypotensive Agents among 5,5-Dimethylhydantoin Derived α1-Adrenoceptors Antagonists

Modulatory Effect of Croton heliotropiifolius Kunth Ethanolic Extract on Norfloxacin Resistance in Staphylococcus aureus

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