Benzocyclohexane oxide derivatives and neolignans from Piper betle inhibit efflux-related resistance in Staphylococcus aureus

Abstract

This research seeks to address the problem of methicillin-resistant Staphylococcus aureus (MRSA) by discovering synergistic antibacterial natural substances from traditional Chinese herbs using antibacterial bioassays. Six compounds, including three neolignans (À)-acuminatin (1), (À)-denudatin B (2), puberulin D (3), and three benzocyclohexane oxide derivatives ferrudiol (4), ellipeiopsol B (5) and zeylenol (6), were isolated and purified by silica gel and reverse-phase silica gel column chromatography, and the chemical structures were determined through NMR spectroscopy, MS, together with CD and calculated CD spectroscopic methods. Synergistic activity was determined using strain SA1199B, a strain that overexpresses the major S. aureus multidrug transporter, NorA. Compounds 1-6 showed synergistic activity combined with norfloxacin against SA1199B, with FICI values of 0.13, 0.25, 0.25, 0.52, 0.08 and 0.27 respectively. The synergistic effects of the benzocyclohexane oxide derivatives with norfloxacin were further demonstrated through strain growth kinetics experiments. In the mechanistic experiment, the compounds showed significant accumulation and/or inhibition effects for EtBr efflux in SA1199B.These active compounds showed no toxicity to HEK293T cells at a concentration of 100 mM in the cytotoxicity evaluation experiments. Combined with efflux pump inhibitors, classic antibiotics that are substrates for efflux pumps may yet play a role in the therapy of drug-resistant bacteria where a lower dose could result in improved safety. View Article Onlinea (1) FICI # 0.5 is dened as synergy; 0.5 < FICI # 1 as additive; 0.5 < FICI # 4 as indifferent; 4 < FICI as antagonistic.(2) All six compounds have no direct inhibitory effects on ve strains and no synergetic effects combined with the other four strains, so data about those was not listed in above table. 43522 | RSC Adv., 2016, 6, 43518-43525This journal is

Essential Oil, Extracts, and Sesquiterpenes Obtained From the Heartwood of Pilgerodendron uviferum Act as Potential Inhibitors of the Staphylococcus aureus NorA Multidrug Efflux Pump

“…Oluwatuyi et al (2004) demonstrated that the abietane diterpenes, carnosic acid and carnosol, which were isolated from Rosmarinus officinalis , had modest EPI activity. Carnosic acid decreased the MIC values of erythromycin against RN4220 (pUL5054; msrA ++) by eightfold and caused a twofold decreased in the EtBr MIC against the SA-1199B strain of S. aureus , which overexpresses the norA gene that encodes the NorA MDR efflux pump (Sun et al, 2016), and that of tetracycline against the XU212 strain of S. aureus , which possesses the TetK tetracycline efflux protein (Sun et al, 2016). However, carnosic acid inhibited EtBr efflux in SA-1199B cells, suggesting that it has weak NorA-inhibitory activity.…”

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

“…In our previous study, neolignans from P. betle were revealed having potent synergistic activity in antibacterial assays against the drug-resistant S. aureus strain SA1199B 10 . In this research, all compounds isolated from P. betle were guided by synergistic antimicrobial screening against SA1199B, but none showed direct inhibitory activity at a concentration of 256 µg/mL.…”

Synergistic effect of ampicillin and dihydrobenzofuran neolignans (myticaganal C) identified from the seeds of Myristica fragrans Houtt. against Escherichia coli

“…[ 5 6 7 ] These compounds have been reported as antibacterial agents against pathogens. [ 8 9 ] Myristica fragrans Houtt. is an important plant source of neolignans used for preventing cancer and leishmaniasis.…”