Synergistic Antibacterial and Antibiotic Effects of Bisbenzylisoquinoline Alkaloids on Clinical Isolates of Methicillin-Resistant Staphylococcus Aureus (MRSA)

Abstract

The antibacterial activity of two bisbenzylisoquinoline alkaloids, tetrandrine (Tet) and demethyltetrandrine (d-Tet), alone and in combination with the antibiotics ampicillin (AMP), azithromycin (AZM), cefazolin (CFZ) and levofloxacin (LEV) against 10 clinical isolates of staphylococcal chromosomal cassette mec (SCCmec) III type methicillin-resistant Staphylococcus aureus (MRSA) was studied. Susceptibility to each agent alone was tested using a broth microdilution method. The chequerboard and time-kill tests were used for the combined evaluations. The minimal inhibitory concentrations/minimal bactericidal concentrations (MICs/MBCs, μg/mL) ranges alone were 64–128/256–1,024 for both Tet and d-Tet. Significant synergies against 90% of the isolates were observed for the Tet/CFZ combination, with their MICs being reduced by 75–94% [fractional inhibitory concentration indices (FICIs) ranged from 0.188 to 0.625], respectively. An additive bactericidal result was also observed for the Tet (d-Tet)/CFZ combination in the time-kill experiments. These results demonstrated that Tet and d-Tet enhanced the in vitro inhibitory efficacy of CFZ. Their potential for combinatory therapy of patients infected with MRSA warrants further pharmacological investigation.

Pharmacodynamic Interaction ofQuercus infectoriaGalls Extract in Combination with Vancomycin against MRSA Using Microdilution Checkerboard and Time-Kill Assay

“…However, our results were similar to a study that demonstrated that the checkerboard method produced significant synergies for the flavanonol rhamnoside in combination with levofloxacin, but changed to additivity in the time-kill dynamic confirmation test against MRSA [33]. The same finding was observed for the bisbenzylisoquinoline alkaloid in combination with cefazolin against clinical isolates of MRSA [34]. …”

Biological activities and antibacterial biomarker of <i>Sesbania grandiflora</i> bark extract

“…Many previous studies have shown that the combination of phytochemical compounds in natural products revealed synergistic effect (41,42). The synergistic effect indicate that associating of several compounds in the plant could give the stronger activity than the individual active compound for that activity (43)(44)(45). The antibacterial potency of EAF that significantly higher than the sum of total different fractions might be explained by the synergistic effect of many compounds existing in the extract.…”

Mechanistic understanding enables the rational design of salicylanilide combination therapies for Gram-negative infections

“…Subcultures of E. coli BW25113 were grown to late exponential phase (OD 600 ~1) in MHB with 10 mM EDTA (to facilitate diSC 3 (5) cell entry). Cells were harvested by centrifugation, washed twice in buffer (5 mM HEPES, pH 7.2, 20 mM glucose, 5% DMSO), and then resuspended in buffer to a final OD 600 = 0.085 with 1 μM DiSC3(5). For valinomycin, 100 mM KCl was added to the cell suspension containing diSC 3 (5).…”

“…, enhanced efficacy over the predicted additive effects (3, 4). Synergistic combination therapies can kill microbes that are resistant to one of the drugs in the pair, may slow the evolution of resistance (5–7), and can facilitate the use of lower doses of each drug, thus reducing side effects and adverse reactions (8). The identification of synergistic drug combinations, however, is challenging due to the infrequency of synergistic relationships and the substantial scale of combinatorial drug screening ( e.g ., for a collection of 1,000 compounds, 499,500 pairwise combinations are possible, even before considering optimal relative concentrations) (3, 4).…”