Antimicrobial activity of Phyllanthus amarus Schumach. &amp; Thonn and inhibition of the NorA efflux pump of Staphylococcus aureus by Phyllanthin

Ribeiro, Alessandra Maria Braga; Sousa, Jonas Nascimento de; Costa, Luciana Muratori; Oliveira, Felipe Araújo de Alcântara; Santos, Raimunda Cardoso dos; Nunes, Aline Suelen Silva; Silva, Wanderson O.; Cordeiro, Paulo Jorge Marques; Neto, José de Sousa Lima; Siqueira-Júnior, José P.; Kaatz, Glenn W.; Barreto, Humberto Medeiros; Oliveira, Aldeídia Pereira de

doi:10.1016/j.micpath.2019.03.012

Cited by 35 publications

(10 citation statements)

References 30 publications

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“…Despite not showing activity against this specific strain, addition of these compounds to the growth medium at 256 μg/mL (MIC 1/4) potentiated the antibacterial effect of norfloxacin against the SA-1199B strain, reducing the MIC values for norfloxacin by at least two-fold (Table 1). Modulating effect on the resistance to norfloxacin could be explained by inhibition of NorA efflux pump overproduced by SA-1199B, as already reported for several compound classes, such as alkamides [18], chalcones [44][45][46], flavonoids [47][48][49][50], and lignans [51]. In fact, visnagin, and khellin showed a modulating effect like that exhibited by the known NorA inhibitor chlorpromazine.…”

Section: Resultssupporting

confidence: 64%

Modulation of Drug Resistance by Furanochromones in NorA Overexpressing Staphylococcus Aureus

Rodrigues

Borges

Nogueira

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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Khellin and visnagin are natural furanochromones that photoreact with DNA. Khellin has been used in the treatment of vitiligo and psoriasis, as well as in the treatment of angina pectoris and asthma due to its potent action as a coronary vasodilator and antispasmodic agent. The present study aimed to investigate whether the compounds khellin and visnagin act as inhibitors of NorA protein, an efflux pump overproduced by the strain of Staphylococcus aureus SA-1199B that confers resistance to the fluoroquinolones, such as norfloxacin and ciprofloxacin. These substances alone did not show antibacterial activity against the strain tested. On the other hand, when these compounds were added to the culture medium at subinhibitory concentration, they were able to reduce the minimum inhibitory concentration (MIC) of norfloxacin, ethidium bromide, as well as berberine, suggesting that these compounds are modulating agents of norfloxacin resistance, possibly due to NorA inhibition. Molecular docking analysis showed that both khellin and visnagin form hydrogen bonds with Arg310, an important residue in the interaction between NorA and its substrates, supporting the hypothesis that these compounds are NorA inhibitors. These results suggest a possible application of khellin and visnagin as adjuvants to norfloxacin in the treatment of infections caused by strains of S. aureus that overproduce NorA.

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Section: Resultssupporting

confidence: 64%

Modulation of Drug Resistance by Furanochromones in NorA Overexpressing Staphylococcus Aureus

Rodrigues

Borges

Nogueira

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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“…NorA inhibition by chalcones was strongly influenced by the methoxylation degree, since chalcone 4 is trimethoxylated and showed the better modulating activity. The presence of methoxy groups has been reported as a factor that favors the interaction of a compound with NorA [38]. Another previous study found that the addition of methoxyl groups increased the lipophilicity of the studied flavanones, as well as that the tetramethoxylated compound had a greater modulatory effect on Norfloxacin resistance in SA1199-B than other di-or trimethoxylated compounds [39].…”

Section: A) B)mentioning

confidence: 87%

Chalcones Isolated from Arrabidaea brachypoda Flowers as Inhibitors of NorA and MepA Multidrug Efflux Pumps of Staphylococcus aureus

et al. 2020

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Bacterial resistance to antibiotics has become a public health issue around the world. The present study aimed to evaluate the antibacterial activity of chalcones isolated from flowers of Arrabidaea brachypoda, and their potential as efflux pump inhibitors of Staphylococcus aureus efflux pumps. Microdilution assays were performed with natural products from A. brachypoda. Chalcones 1, 3, 4, and 5 did not show intrinsic antimicrobial activity against all S. aureus strains tested, but they were able to potentiate the Norfloxacin action against the SA1199-B (norA) strain, with a better modulating action for the 4 trimethoxylated chalcone. All chalcones were also able to potentiate the action of EtBr against SA1199-B strain, suggesting a potential NorA inhibition. Moreover, chalcone 4 was able to interfere in the activity of MepA, and interfered weakly in the QacA/B activity. Molecular docking analyzes showed that tested chalcones are capable of binding in the hydrophobic cavity of NorA and MepA, in the same Norfloxacin binding site, indicating that chalcone 4 compete with the antibiotic for the same NorA and MepA binding sites. Association of chalcone 4 with Norfloxacin could be an alternative against multidrug resistant S. aureus over-productive of NorA or MepA.

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“…Apart from phage endolysins, identifying efflux pump inhibitory molecules, e.g., P-glycoproteins, would be another approach to combat the continuous rise of MDR pathogens [35]. In addition, an array of recent studies has also demonstrated that some natural products such as DCMF from M. caesalpiniifolia and P. amarus ethanoic extracts could function as pump inhibitors and interact with conventional antibiotics fighting against pathogenic resistance [36,37]. These natural or synthetic pumps inhibitors can also be covalently joined together as a hybrid, which indeed showed surprisingly in vitro and in vivo antimicrobial activity [38].…”

Section: Discussionmentioning

confidence: 99%

Design, Overproduction and Purification of the Chimeric Phage Lysin MLTphg Fighting against Staphylococcus aureus

Liu

Deng

et al. 2020

Processes

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With the increasing spread of multidrug-resistant bacterial pathogens, it is of great importance to develop alternatives to conventional antibiotics. Here, we report the generation of a chimeric phage lysin, MLTphg, which was assembled by joining the lysins derived from Meiothermus bacteriophage MMP7 and Thermus bacteriophage TSP4 with a flexible linker via chimeolysin engineering. As a potential antimicrobial agent, MLTphg can be obtained by overproduction in Escherichia coli BL21(DE3) cells and the following Ni-affinity chromatography. Finally, we recovered about 40 ± 1.9 mg of MLTphg from 1 L of the host E. coli BL21(DE3) culture. The purified MLTphg showed peak activity against Staphylococcus aureus ATCC6538 between 35 and 40 °C, and maintained approximately 44.5 ± 2.1% activity at room temperature (25 °C). Moreover, as a produced chimera, it exhibited considerably improved bactericidal activity against Staphylococcus aureus (2.9 ± 0.1 log10 reduction was observed upon 40 nM MLTphg treatment at 37 °C for 30 min) and also a group of antibiotic-resistant bacteria compared to its parental lysins, TSPphg and MMPphg. In the current age of growing antibiotic resistance, our results provide an engineering basis for developing phage lysins as novel antimicrobial agents and shed light on bacteriophage-based strategies to tackle bacterial infections.

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Antimicrobial activity of Phyllanthus amarus Schumach. & Thonn and inhibition of the NorA efflux pump of Staphylococcus aureus by Phyllanthin

Cited by 35 publications

References 30 publications

Modulation of Drug Resistance by Furanochromones in NorA Overexpressing Staphylococcus Aureus

Modulation of Drug Resistance by Furanochromones in NorA Overexpressing Staphylococcus Aureus

Chalcones Isolated from Arrabidaea brachypoda Flowers as Inhibitors of NorA and MepA Multidrug Efflux Pumps of Staphylococcus aureus

Design, Overproduction and Purification of the Chimeric Phage Lysin MLTphg Fighting against Staphylococcus aureus

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