N,N′-disubstituted cinnamamide derivatives potentiate ciprofloxacin activity against overexpressing NorA efflux pump Staphylococcus aureus 1199B strains

Radix, Sylvie; Jordheim, Anne Doléans; Rocheblave, Luc; N'Digo, Serge; Prignon, Anne-Laure; Commun, Carine; Michalet, Serge; Dijoux‐Franca, Marie‐Geneviève; Mularoni, Angélique; Walchshofer, Nadia

doi:10.1016/j.ejmech.2018.03.028

Cited by 12 publications

(7 citation statements)

References 30 publications

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“…The same MIC reduction of ciprofloxacin was observed for compound 11 (Figure ) at 3.1 µM, while compound 12 (Figure ) had an MPC 4 of 0.14 µM . Cinnamamide derivatives were also reported to potentiate the activity of ciprofloxacin against SA1199B, with an MPC 4 of 19.1 µM for the most active compound …”

Section: Efflux Pump Inhibitors Of Selected Clinically Relevant Pathomentioning

confidence: 93%

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Efflux pump inhibitors of clinically relevant multidrug resistant bacteria

Lamut

Mašič

Kikelj

et al. 2019

Medicinal Research Reviews

141

116

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Bacterial infections are an increasingly serious issue worldwide. The inability of existing therapies to treat multidrug‐resistant pathogens has been recognized as an important challenge of the 21st century. Efflux pumps are important in both intrinsic and acquired bacterial resistance and identification of small molecule efflux pump inhibitors (EPIs), capable of restoring the effectiveness of available antibiotics, is an active research field. In the last two decades, much effort has been made to identify novel EPIs. However, none of them has so far been approved for therapeutic use. In this article, we explore different structural families of currently known EPIs for multidrug resistance efflux systems in the most extensively studied pathogens (NorA in Staphylococcus aureus, AcrAB‐TolC in Escherichia coli, and MexAB‐OprM in Pseudomonas aeruginosa). Both synthetic and natural compounds are described, with structure‐activity relationship studies and optimization processes presented systematically for each family individually. In vitro activities against selected test strains are presented in a unifying manner for all the EPIs described, together with the most important toxicity, pharmacokinetic and in vivo efficacy data. A critical evaluation of lead‐likeness characteristics and the potential for clinical development of the most promising inhibitors of the three efflux systems is described. This overview of EPIs is a good starting point for the identification of novel effective antibacterial drugs.

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Section: Efflux Pump Inhibitors Of Selected Clinically Relevant Pathomentioning

confidence: 93%

“…MPC 4 of 19.1 µM for the most active compound 177. F I G U R E 3 13-CPTC(7) showing modification of the initial tetracycline scaffold (marked green) [Color figure can be viewed at wileyonlinelibrary.com]Reserpine is a plant-derived indole alkaloid from the roots of Rauwolfia spp.…”

mentioning

confidence: 99%

Efflux pump inhibitors of clinically relevant multidrug resistant bacteria

Lamut

Mašič

Kikelj

et al. 2019

Medicinal Research Reviews

141

116

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“…SA1199B is a norfloxacin-resistant strain and overexpresses the norA gene encoding the NorA MDR efflux pump . Compounds demonstrating synergistic activity ( 5 , 12 , and 14 – 19 ) were tested for inhibition of EtBr efflux using a fluorometric method.…”

Section: Results and Discussionmentioning

confidence: 99%

“…It is a leading cause of nosocomial resistance despite the availability of effective antimicrobials . In norfloxacin-resistant Staphylococcus aureus , the NorA efflux pump has the capability to efflux diverse antibiotics, such as fluoroquinolones and dyes such as acridine and ethidium bromide (EtBr), and contributes to MDR in the genus Staphylococcus …”

Section: Introductionmentioning

confidence: 99%

“…2 In norfloxacin-resistant Staphylococcus aureus, the NorA efflux pump has the capability to efflux diverse antibiotics, such as fluoroquinolones and dyes such as acridine and ethidium bromide (EtBr), and contributes to MDR in the genus Staphylococcus. 3 Among the currently approved antimicrobials, the last discovery of a new drug class occurred more than 30 years ago. 4 To bridge this discovery gap, various strategies have been investigated including the use of synergism to enhance the activity of an antibacterial.…”

Section: ■ Introductionmentioning

confidence: 99%

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Neolignans from Piper betle Have Synergistic Activity against Antibiotic-Resistant Staphylococcus aureus

et al. 2021

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A phytochemical investigation of an extract of the leaves of Piper betle, guided by a synergistic antibacterial screen, led to the isolation and structural elucidation of 10 new neolignans, Pibeneolignan A−J (1−10), together with 11 known compounds. The structures and absolute configurations of the new compounds were elucidated on the basis of spectroscopic data, single-crystal X-ray diffraction analysis, and experimental and calculated ECD investigations. Compounds 1 and 2 are new naturally occurring neolignan skeleton, based on the cyclohept-2-ene-l,4-dione framework. We propose that these natural products are biosynthetically formed from bicyclic [3.2.1] neolignans by oxidative cleavage and ring opening at C-1′ and C-2′. Among these compounds, 9, 13, 15 and 16 in combination with norfloxacin against an effluxing S. aureus strain (SA1199B), exhibited significant synergistic activity with fractional inhibitory concentration indices (FICIs) of 0.078, 0.156, 0.125 and 0.25 respectively. Bacterial growth curves, ethidium bromide (EtBr) efflux, and qRt-PCR were further employed to verify their synergistic antibacterial mechanism. Furthermore, computational molecular modeling suggested the binding of compounds 14-17 and 19 to the active site of the modeled structure of the NorA efflux pump, which is the main efflux pump in SA1199B.

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