Membrane Active Phenylalanine Conjugated Lipophilic Norspermidine Derivatives with Selective Antibacterial Activity

Konai, Mohini M.; Ghosh, Chandradhish; Yarlagadda, Venkateswarlu; Samaddar, Sandip; Haldar, Jayanta

doi:10.1021/jm5013566

Cited by 114 publications

(121 citation statements)

References 47 publications

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“…LPPOs belong to the growing family of small molecule antibacterial peptide mimetics, that include cationic steroid antibiotics [48][49][50], phenylalanine lipophilic norspermidine derivatives [51], xanthone-based, membrane-targeting antimicrobials [52], 2-((3-(3,6-dichloro-9H-carbazol-9-yl)-2-hydroxypropyl)amino)-2-(hydroxymethyl)propane-1,3-diol (DCAP) [53], arylamide foldamers [54,55], and a promising synthetic, bactericidal antimicrobial peptide, which degrades the membranes of harmful micro-organisms coded as LTX-109 [56]. These compounds are structurally heterogenic but they all are amphiphilic molecules containing a lipophilic part and hydrophilic part containing usually positive charge(s).…”

Section: Discussionmentioning

confidence: 99%

Insights into the mechanism of action of bactericidal lipophosphonoxins

Panova¹,

Zborníková²,

Šimák³

et al. 2014

Collection Symposium Series

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The advantages offered by established antibiotics in the treatment of infectious diseases are endangered due to the increase in the number of antibiotic-resistant bacterial strains. This leads to a need for new antibacterial compounds. Recently, we discovered a series of compounds termed lipophosphonoxins (LPPOs) that exhibit selective cytotoxicity towards Gram-positive bacteria that include pathogens and resistant strains. For further development of these compounds, it was necessary to identify the mechanism of their action and characterize their interaction with eukaryotic cells/organisms in more detail. Here, we show that at their bactericidal concentrations LPPOs localize to the plasmatic membrane in bacteria but not in eukaryotes. In an in vitro system we demonstrate that LPPOs create pores in the membrane. This provides an explanation of their action in vivo where they cause serious damage of the cellular membrane, efflux of the cytosol, and cell disintegration. Further, we show that (i) LPPOs are not genotoxic as determined by the Ames test, (ii) do not cross a monolayer of Caco-2 cells, suggesting they are unable of transepithelial transport, (iii) are well tolerated by living mice when administered orally but not peritoneally, and (iv) are stable at low pH, indicating they could survive the acidic environment in the stomach. Finally, using one of the most potent LPPOs, we attempted and failed to select resistant strains against this compound while we were able to readily select resistant strains against a known antibiotic, rifampicin. In summary, LPPOs represent a new class of compounds with a potential for development as antibacterial agents for topical applications and perhaps also for treatment of gastrointestinal infections.

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Section: Discussionmentioning

confidence: 99%

Insights into the mechanism of action of bactericidal lipophosphonoxins

Panova¹,

Zborníková²,

Šimák³

et al. 2014

Collection Symposium Series

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“…Percentage of Inhibition = OD control -OD Experimental X 100 OD control Confocal Imaging Prevention of biofilm formation was confirmed using a microscopic technique [9]. Briefly, strains were allowed to grow on round glass slides (diameter 1 cm) placed in 24-well polystyrene plates supplemented with the quercetin fraction (200 ug/ml) and incubated for 24 h at 37°C and stained with acridine orange solution (v/v) for 20 min at room temperature.…”

Section: Biofilm Prevention Potential: Disruption Of Preformed Biofilmmentioning

confidence: 99%

Targeting biofilm inhibition using Quercetin – Interaction with bacterial cell membrane and ROS mediated biofilm control

Sarangapani¹,

Jayachitra²

2018

FFHD

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Citation: Sreelatha S., Jayachitra A., Targeting biofilm inhibition using Quercetin -Interaction with bacterial cell membrane and ROS mediated biofilm control. Functional Foods in Health and Disease 2018; 8(6): 292-306 ABSTRACT Background: Quercetin is an active nutraceutical ingredient widely distributed in foods, vegetables, fruits, and more. Quercetin is a versatile functional food with extensive protective effects against many infectious and degenerative diseases due to their antioxidant activities. Apsergillus niger is a filamentous fungus and the most abundant mold found in the environment. This fungus has been the source of several bioactive compounds and industrial enzymes through biotransformation. Aim:In this report we emphasized the potential of Aspergillus species for the selective conversion of rutin to quercetin, which involved stereoselective and regiospecific reactions with enhanced production and minimization of the formation of toxic wastes. This fungal microbe was able to transform the complex structure of rutin to quercetin with remarkable catalytic activity for the reaction with high product yield. The quercetin produced demonstrated the ability to inhibit biofilm formation and eradicate established biofilm involving the production of reactive oxygen species (ROS) indicative of membrane activity. These results suggest quercetin may have implications in biofilm control targeting reactive oxygen species as a novel therapeutic strategy. Methods: Quercetin was synthesized by microbial biotransformation recruiting Aspergillus niger.The synthesis of quercetin was compared with the chemical process. Furthermore, the quercetin produced by the biotransformation process was characterized by high performance thin layer liquid chromatography. The quercetin produced was assessed for biological activities. The antimicrobial activity, hemolytic activity, inhibition of biofilm by crystal violet staining, and cell viability by confocal laser scanning microscope was assessed. The membrane interaction effect and oxidant scavenging effect by DPPH, Intracellular ROS release, and lipid peroxidation was measured. Results:Quercetin produced by microbial transformation demonstrated antimicrobial activity against S. aureus by effectively inhibiting the growth and dispersion of preformed biofilms. Quercetin demonstrated a significant free radical scavenging activity and significant inhibition of lipid peroxidation. Significant release of reactive oxygen species was observed in bacterial cells.

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“…Lipophilic norspermidine derivatives as antibacterial agents also offer hope as potential solution to the problem of bacterial resistance as the membrane-active nature imparts low propensity for the development of resistance [20]. Phenylalanine conjugated aliphatic norspermidine derivatives, as membrane active antimicrobial agents, displayed improved antibacterial activity compared to nonconjugated aliphatic norspermidine derivatives.…”

Section: Introductionmentioning

confidence: 99%

“…Phenylalanine conjugated aliphatic norspermidine derivatives, as membrane active antimicrobial agents, displayed improved antibacterial activity compared to nonconjugated aliphatic norspermidine derivatives. Some derivatives with dodecanoyl substituent showed over 250-fold more antimicrobial activity against VRE compared to vancomycin, last resort antibiotic for Gram-positive bacterial infection [20]. These compounds primarily damage bacterial cell membrane and kill the bacteria very quickly, below 15 min.…”

Section: Introductionmentioning

confidence: 99%