Synergistic antibacterial activity of the combination of the alkaloid sanguinarine with EDTA and the antibiotic streptomycin against multidrug resistant bacteria

Abstract

The combination of drugs, which interfere with different molecular targets, can be an important strategy to combat multidrug resistant bacteria.

Modes of Action of Herbal Medicines and Plant Secondary Metabolites

“…In most cases, it was almost impossible to define a single SM, which could explain the bioactivity of the extract or its application in traditional medicine. It is likely that the activity of an extract can be due to synergistic interactions of several SM present, which cannot be detected when single compounds are evaluated alone [68,69,70,71,72,73,74,75,76,77,78,79,80,81]. Moreover, these extracts are often used to treat a broad spectrum of health disorders and not a single condition.…”

In vitro Activity of Robenidine Analog NCL195 in Combination With Outer Membrane Permeabilizers Against Gram-Negative Bacterial Pathogens and Impact on Systemic Gram-Positive Bacterial Infection in Mice

“…To assess potential synergistic activity of NCL195, MICs for a range of Gram-negative ATCC strains and clinical isolates of K. pneumoniae , E. coli , A. baumannii , and P. aeruginosa were determined in the presence or absence of 23.2–11,400 μg/mL (0.06–30 mM) of EDTA and 0.25–128 μg/mL of PMBN or PMB in a modified standard checkerboard assay as described previously ( Hamoud et al, 2015 ; Khazandi et al, 2019 ). Briefly, antimicrobial stock solutions were prepared at a concentration of 25.6 mg/mL in DMSO for NCL195, 12.8 mg/mL in Milli-Q water for PMBN and PMB, and 30 mM in Milli-Q water for EDTA.…”

Naturally-Occurring Alkaloids of Plant Origin as Potential Antimicrobials against Antibiotic-Resistant Infections

“…For this reason, it can be assumed that it presents a similar antibacterial activity by the inhibition of the Z-ring formation on MRSA, MSSA vancomycin-sensitive (VSE) and vancomycin-resistant strains (VRE) of E. faecalis [ 123 , 124 , 125 , 126 ] and by the intercalation with bacterial DNA [ 127 , 128 , 129 ]. Hamoud et al investigated the antimicrobial activity of individual drugs, e.g., the DNA intercalating sanguinarine, the chelator ethylenediaminetetraacetic acid (EDTA) and the antibiotic streptomycin; of two-drugs interaction between EDTA or antibiotics and sanguinarine in comparison with the three-drug activities against several Gram-positive and Gram-negative bacteria, including multi-resistant clinical isolates [ 102 , 127 ]. Among the three drugs, sanguinarine demonstrated the strongest antibacterial activity against Gram-positive bacteria with MIC values ranging between 0.5 μg/mL against S. epidermidis and 8 μg/mL against VRE, whereas streptomycin showed the strongest activity against Gram-negative strains.…”

“…Interestingly, the three-drug combination displayed synergistic activity against almost all the strains (except methicillin- resistant S. aureus ), as well as a strong reduction (2–16 times) in the effective doses (i.e., MIC of drug alone/MIC drug in combination) of sanguinarine, EDTA and streptomycin. The authors postulated that the synergistic interactions are due to different modes of action of the individual drugs: EDTA as a chelating agent disturbs the permeability of the bacteria cell wall leading to a higher influx of sanguinarine and streptomycin into the bacterial cell [ 102 , 127 ]. Choi et al reported that a structural homolog of sanguinarine, the 6-methoxydihydrosanguinarine ( Table 4 ), isolated from Hylomecon hylomeconoides, displayed an antibacterial activity higher than that of the antibiotic ampicillin against S. aureus ATCC 25923 (MSSA), S. aureus ATCC 33591 (MRSA) and DPS-1 (clinical MRSA) strains with MICs in the range of 1.9–3.9 μg/mL.…”