Ferulic acid derivative inhibits NorA efflux and in combination with ciprofloxacin curtails growth of MRSA in vitro and in vivo

Sundaramoorthy, Niranjana Sri; Mitra, Kartik; Ganesh, Jayasankari Senthil; Makala, Himesh; Lotha, Robert; Bhanuvalli, Shamprasad R.; Ulaganathan, Venkatasubramanian; Tiru, Vaidehi; Sivasubramanian, Aravind; Nagarajan, Saisubramanian

doi:10.1016/j.micpath.2018.08.022

Cited by 31 publications

(15 citation statements)

References 54 publications

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“…The cells were de-energized, EtBr was added and then glucose was added to re-energize the cells, which would activate efflux. Resulting fluorescent intensity was measured with Ex 360 nm and Em 590 nm as reported earlier (Sundaramoorthy et al 2018). The increase in fluorescent intensity of EtBr was taken as a measure of efflux inhibition activity.…”

Section: Methodsmentioning

confidence: 99%

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Ursolic acid inhibits colistin efflux and curtails colistin resistant Enterobacteriaceae

et al. 2019

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Colistin resistance in Enterobacteriaceae especially Klebsiella pneumoniae and Escherichia coli is driving the evolution of pan drug resistant strains. Screening a library of 13 plant nutraceuticals led to the identification of acetyl shikonin and ursolic acid, which exhibited synergy with colistin against extremely drug resistant (XDR) clinical strains of E. coli (U3790) and K. pneumoniae (BC936). Ursolic acid caused a significant colistin MIC reversal of 16-fold in U3790 and 4-fold in BC936 strains. Ursolic acid also potentiated the bactericidal effect of colistin against both U3790 and BC936 by causing ~ 4 to 4.5 log fold decline in CFU of both clinical isolates in a time kill assay. At 2× minimum effective concentration, ursolic acid was non-toxic to zebrafish as evidenced by brain and liver enzyme profiles and by histopathology studies. In combination with colistin, ursolic acid reduced bacterial bioburden of U3790/BC936 by 1–1.58 log fold from the infected muscle tissue of zebrafish. Mechanistic explorations via studies on real time efflux, membrane potential and intracellular accumulation of dansyl chloride tagged colistin revealed that colistin efflux is inhibited by ursolic acid. In addition, ursolic acid also enhanced outer membrane permeability which probably facilitates colistin’s attack on outer and inner membranes. Our study shows that ursolic acid synergizes with colistin by inhibiting colistin efflux in Enterobacteriaceae that helps to curtail colistin resistant Enterobacteriaceae . Electronic supplementary material The online version of this article (10.1186/s13568-019-0750-4) contains supplementary material, which is available to authorized users.

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Section: Methodsmentioning

confidence: 99%

“…Ursolic acid at sub-MIC concentration was used along with varying concentrations of colistin and incubated for 18–24 h at 37 °C. The fold reduction in MIC (MIC reversal) of colistin when combined with ursolic acid was determined as modulation factor as reported earlier (Lowrence et al 2016; Sundaramoorthy et al 2018).…”

Section: Methodsmentioning

confidence: 99%

Ursolic acid inhibits colistin efflux and curtails colistin resistant Enterobacteriaceae

et al. 2019

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“…6). Above all, CCCP being a protonophore is known for its toxicity 41 . Moreover, fish administered with CCCP at recommended concentration died within 24 h proving the toxicity of CCCP.…”

Section: Discussionmentioning

confidence: 99%

Restoring colistin sensitivity in colistin-resistant E. coli: Combinatorial use of MarR inhibitor with efflux pump inhibitor

Sundaramoorthy

Suresh

Ganesan

et al. 2019

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Antibiotics like colistin are the last resort to deal with infections by carbapenem-resistant Enterobacteriaceae (CREB). Resistance to colistin severely restricts therapeutic options. To tackle this dire situation, urgent measures to restore colistin sensitivity are needed. in this study, whole-genome sequencing of colistin-resistant E. coli strain was performed and the genome analysis revealed that the strain belonged to the sequence type ST405. Multiple mutations were observed in genes implicated in colistin resistance, especially those related to the L-Ara-4-N pathway but mgrB was unmutated and mcr1-9 genes were missing. MarR inhibitor salicylate was used to re-sensitize this strain to colistin, which increased the negative charge on the cell surface especially in colistin resistant E. coli (U3790 strain) and thereby facilitated a decrease in colistin MIC by 8 fold. It is indeed well known that MarR inhibition by salicylate triggers the expression of AcrAB efflux pumps through MarA. So, in order to fully restore colistin sensitivity, a potent efflux pump inhibitor (BC1), identified earlier by this group was employed. The combination of colistin with both salicylate and BC1 caused a remarkable 6 log reduction in cell counts of U3790 in time-kill assay. Infection of muscle tissue of zebrafish with U3790 followed by various treatments showed that the combination of colistin + salicylate + BC1 was highly effective in reducing bioburden in infected muscle tissue by 4 log fold. Thus, our study shows that a combination of MarR inhibitor to enhance colistin binding and efflux pump inhibitor to reduce colistin extrusion was highly effective in restoring colistin sensitivity in colistin-resistant clinical isolate of E. coli in vitro and in vivo. Antimicrobial resistance (AMR) poses a grave threat to public health and is attributed as the third major cause of mortality worldwide. Rise in infections caused by multidrug-resistant (MDR) pathogens prompted WHO to declare a list of 12 priority AMR pathogens in 2017, of which, carbapenem-resistant Enterobacteriaceae (Escherichia coli, Klebsiella spp, Serratia spp, Proteus spp) fall under critical priority group 1. Due to rising AMR menace, new antimicrobial agents or resistance modulatory agents to curtail AMR are urgently required. Recently, WHO has released its first report on AMR surveillance, which reveals an alarming trend of widespread dissemination of resistant traits among microbes globally, wherein resistance to commonly used antibiotics were found to range from 0-82% 2. Carbapenem-resistant Enterobacteriaceae (CREB) is becoming resistant to almost all antibiotics and its clinical outcomes are also poor 3,4. Among Enterobacteriaceae, Escherichia coli tops the list in causing a wide range of clinical infections due to their high prevalence, multidrug resistance and most importantly, rapid acquisition/ transfer of resistance traits by horizontal gene transfer 5,6. Colistin is a drug of last resort for CREBs 7. Colistin resistance implies a pan drug resistant state, with...

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“…TFA has antibacterial property as well as antioxidant feature. In the previous study, researchers have proved the ability of herbal compounds to be utilized as adjuvants together with antibacterial drugs [7].…”

Section: Introductionmentioning

confidence: 99%

Vesicular Formation of Trans-Ferulic Acid: an Efficient Approach to Improve the Radical Scavenging and Antimicrobial Properties

et al. 2021

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Purposes Reactive oxygen species production is harmful to human’s health. The presence of antioxidants in the body may help to diminish reactive oxygen species. Trans-ferulic acid is a good antioxidant, but its low water solubility excludes its utilization. The study aims to explore whether a vesicular drug delivery could be a way to overcome the poor absorption of trans-ferulic acid hence improving its antimicrobial efficiency and antioxidant effect. Methods Niosomal vesicles containing the drug were prepared by film hydration method. The obtained vesicles were investigated in terms of morphology, size, entrapment efficiency, release behavior, cellular cytotoxicity, antioxidant, cellular protection study, and antimicrobial evaluations. Results The optimized niosomal formulation had a particle size of 158.7 nm and entrapment efficiency of 21.64%. The results showed that the optimized formulation containing 25 μM of trans-ferulic acid could enhance the viability of human foreskin fibroblast HFF cell line against reactive oxygen species production. The minimum effective dose of the plain drug and the niosomal formulation against Staphylococcus aurous (ATCC 29213) was 750 µg/mL and 375 µg/mL, respectively, and for Escherichia coli (ATCC 25922), it was 750 µg/mL and 187/5 µg/mL, respectively. The formulation could also improve the minimum bactericidal concentration of the drug in Staphylococcus aurous, Escherichia coli, and Acinobacter baumannii (ATCC 19606). Conclusion These results revealed an improvement in both antibacterial and antioxidant effects of the drug in the niosomal formulation.

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Ferulic acid derivative inhibits NorA efflux and in combination with ciprofloxacin curtails growth of MRSA in vitro and in vivo

Cited by 31 publications

References 54 publications

Ursolic acid inhibits colistin efflux and curtails colistin resistant Enterobacteriaceae

Ursolic acid inhibits colistin efflux and curtails colistin resistant Enterobacteriaceae

Restoring colistin sensitivity in colistin-resistant E. coli: Combinatorial use of MarR inhibitor with efflux pump inhibitor

Vesicular Formation of Trans-Ferulic Acid: an Efficient Approach to Improve the Radical Scavenging and Antimicrobial Properties

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