Membrane Active Vancomycin Analogues: A Strategy to Combat Bacterial Resistance

Yarlagadda, Venkateswarlu; Akkapeddi, Padma; Manjunath, Goutham B.; Haldar, Jayanta

doi:10.1021/jm500270w

Cited by 150 publications

(173 citation statements)

References 47 publications

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“…The alternative peripheral modification examined was C-terminal amide functionalization with incorporation of either a basic amine capable of protonation or a quaternary ammonium salt. Such modifications have been shown to provide improved antimicrobial activity against vancomycin-resistant organisms and were found to act by disrupting bacterial cell wall membrane integrity, increasing cell permeability, and inducing membrane depolarization (51). Although inspired by the nonselective membrane disruption induced by quaternary ammonium salts, the studies herein provide one such modification that exhibits only a subset of such effects (membrane permeability) and acts by a more specific mechanism not resulting in cell lysis.…”

Section: Resultsmentioning

confidence: 99%

Peripheral modifications of [Ψ[CH ₂ NH]Tpg ⁴ ]vancomycin with added synergistic mechanisms of action provide durable and potent antibiotics

Okano

Isley

Boger

2017

Proc. Natl. Acad. Sci. U.S.A.

176

215

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Significance In a quest for antibiotics that may display durable clinical lifetimes, analogs of the glycopeptide antibiotics, including vancomycin, have been designed that not only directly overcome the molecular basis of existing vancomycin resistance but also contain two added peripheral modifications that endow them with two additional independent mechanisms of actions not found in the parent antibiotics. It is shown that such peripherally and binding pocket-modified vancomycin analogs display little propensity for acquired resistance by vancomycin-resistant Enterococci and that both their antimicrobial potency and durability against such challenges follow trends (three > two > one mechanisms of action) that are now predictable.

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Section: Resultsmentioning

confidence: 99%

Peripheral modifications of [Ψ[CH ₂ NH]Tpg ⁴ ]vancomycin with added synergistic mechanisms of action provide durable and potent antibiotics

Okano

Isley

Boger

2017

Proc. Natl. Acad. Sci. U.S.A.

176

215

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“…The fluorescence intensity was measured at the excitation wavelength of 535 nm and emission wavelength of 617 nm. The uptake of PI was detected [11] by the increase in fluorescence for 10 minutes, which corresponds to the permeabilization of the inner cell membrane.…”

Section: Inhibition Of Biofilm Growth and Developmentmentioning

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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“…The samples were then transferred to cuvettes, and fluorescence was measured using an F-2500 fluorescence spectrophotometer (Hitachi, Japan) at 350 nm (excitation wavelength) and 420 nm (emission wavelength). The inner membrane permeabilization activity of the peptides was measured by the uptake of propidium iodide (PI) (14,15). The collected cells were washed and resuspended as described above, and then 10 M PI was added to the cells and the reaction mixture was incubated for 30 min at 25°C.…”

Section: Organisms the Multidrug-resistant (Mdr) Clinical Isolates Mmentioning

confidence: 99%

The Disulfide Bond of the Peptide Thanatin Is Dispensible for Its Antimicrobial Activity In Vivo and In Vitro

Niu

Zhou

et al. 2016

Antimicrob Agents Chemother

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b Thanatin (THA) displays potent antibiotic activity, especially against extended-spectrum-␤-lactamase (ESBL)-producing Escherichia coli both in vitro and in vivo, with minimal hemolytic toxicity and satisfactory stability in plasma. However, the high cost of thanatin significantly limits its development and clinical application. To reduce the cost of peptide synthesis, a formulation of cyclic thanatin (C-thanatin) called linear thanatin (L-thanatin) was synthesized and its activity was evaluated in vivo and in vitro. Results showed that C-thanatin and L-thanatin MICs did not differ against eight Gram-negative and two Gram-positive bacterial strains. Furthermore, the survival rates of ESBL-producing-E. coli-infected mice were consistent after C-thanatin or L-thanatin treatment at 5 or 10 mg/kg of body weight. Neither C-thanatin nor L-thanatin showed toxicity for human red blood cells (hRBCs) and human umbilical vein endothelial cells (HUVECs) at a concentration as high as 256 g/ml. Results of circular dichroism spectroscopy indicated that the secondary structure of L-thanatin is extremely similar to that of C-thanatin. Membrane permeabilization and depolarization assays showed that C-thanatin and L-thanatin have similar abilities to permeabilize the outer and inner membranes and to induce membrane depolarization in ESBL-producing E. coli. However, neither of them caused significant HUVEC membrane permeability. These findings indicate that the two peptides have similar effects on bacterial cell membranes and that the disulfide bond in thanatin is not essential for its antimicrobial activities in vivo and in vitro. L-thanatin is thus a promising low-cost peptide candidate for treating ESBL-producing E. coli infections. T hanatin (THA) is a cationic antimicrobial peptide that was first discovered in the hemipteran insect Podisus maculiventris.This peptide is composed of 21 amino acids (GSKKPVPIIYCNR RTGKCQRM), with an intramolecular disulfide bridge between the two cysteines at positions 11 and 18. Our previous studies revealed that thanatin exhibits potent antibiotic activity, especially against extended-spectrum-␤-lactamase (ESBL)-producing Esc herichia coli, both in vitro and in vivo, with a low inherent ability to induce microbial resistance, minimal hemolytic toxicity, and high stability in plasma (1, 2).Despite their promise for clinical benefit, the high cost of producing peptide drugs such as thanatin significantly limits their development and clinical application. Compared with conventional antibiotics, the costs of cationic antimicrobial peptides are always prohibitively high for large-scale production (3). Intrachain disulfide bonds exist in many naturally occurring peptides and play important roles in biological activities. However, synthesis of peptide drugs with one or more disulfide bridges is complicated and expensive (4).Previous studies found that the disulfide bonds of protegrin-1 are not essential for its antimicrobial and hemolytic activities in vitro (5). To reduce the cost of thanatin synthes...

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Membrane Active Vancomycin Analogues: A Strategy to Combat Bacterial Resistance

Cited by 150 publications

References 47 publications

Peripheral modifications of [Ψ[CH ₂ NH]Tpg ⁴ ]vancomycin with added synergistic mechanisms of action provide durable and potent antibiotics

Peripheral modifications of [Ψ[CH ₂ NH]Tpg ⁴ ]vancomycin with added synergistic mechanisms of action provide durable and potent antibiotics

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

The Disulfide Bond of the Peptide Thanatin Is Dispensible for Its Antimicrobial Activity In Vivo and In Vitro

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Membrane Active Vancomycin Analogues: A Strategy to Combat Bacterial Resistance

Cited by 150 publications

References 47 publications

Peripheral modifications of [Ψ[CH 2 NH]Tpg 4 ]vancomycin with added synergistic mechanisms of action provide durable and potent antibiotics

Peripheral modifications of [Ψ[CH 2 NH]Tpg 4 ]vancomycin with added synergistic mechanisms of action provide durable and potent antibiotics

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

The Disulfide Bond of the Peptide Thanatin Is Dispensible for Its Antimicrobial Activity In Vivo and In Vitro

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Product

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About

Peripheral modifications of [Ψ[CH ₂ NH]Tpg ⁴ ]vancomycin with added synergistic mechanisms of action provide durable and potent antibiotics

Peripheral modifications of [Ψ[CH ₂ NH]Tpg ⁴ ]vancomycin with added synergistic mechanisms of action provide durable and potent antibiotics