Synthesis and biological evaluation of N-naphthoyl-phenylglyoxamide-based small molecular antimicrobial peptide mimics as novel antimicrobial agents and biofilm inhibitors

Nizalapur, Shashidhar; Ho, Kaitlyn; Kimyon, Önder; Yee, Eugene; Berry, Thomas; Manefield, Mike; Cranfield, Charles G.; Willcox, Mark; Black, David StC.; Kumar, Naresh

doi:10.1039/c6ob00298f

Cited by 27 publications

(29 citation statements)

References 46 publications

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“…Membrane capacitance is directly influenced by membrane thickness and/or the water content at the bilayer. As a positive control, a pore-inducing cathelicidin peptide, LL-37, was later added (Turner et al, 1998;Nizalapur et al, 2016). This addition of LL-37 induced a definite change in membrane conduction and membrane capacitance.…”

Section: Resultsmentioning

confidence: 99%

An examination of microcystin-LR accumulation and toxicity using tethered bilayer lipid membranes (tBLMs)

Facey

Steele

Violi

et al. 2019

Toxicon

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Microcystin-LR (MC-LR) is a potent cyanobacterial toxin responsible for animal and human poisonings worldwide. MC-LR is found in organisms throughout the foodweb, however there is conjecture regarding whether it biomagnifies. Few studies have investigated how MC-LR interacts with lipid membranes, a determinant of biomagnification potential. We tested whether 1 µM MC-LR irreversibly associates with lipid bilayers or causes the creation of pore defects upon short and long-term exposure. Using tethered bilayer lipid membranes (tBLMs), we observed an increase in membrane conduction in tBLMs, representing an interaction of microcystin-LR with the lipid bilayer and a change in membrane packing properties. However, there were minimal changes in membrane capacitance upon short and long-term exposure, and MC-LR exhibited a rapid off-rate. Upon 24 h exposure to the toxin, no lipophilic multimeric complexes were detected capable of altering the toxin's off-rate. There was no evidence of the creation of new pores. This study demonstrates that MC-LR does not irreversibly imbed itself into lipids membranes after short or long-term exposure and suggests MC-LR does not biomagnify through the food web via lipid storage.

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Section: Resultsmentioning

confidence: 99%

An examination of microcystin-LR accumulation and toxicity using tethered bilayer lipid membranes (tBLMs)

Facey

Steele

Violi

et al. 2019

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“…To test how selected potent phenylglyoxamide compounds ( 27 a, 26 b , 34 d , 35 d ) might interact with cell membranes, tethered bilayer lipid membrane (tBLM) technology was used in conjunction with electrical impedance spectroscopy ,. By anchoring a lipid membrane onto a gold substrate, it is possible to measure changes in intrinsic membrane conduction in real time upon addition of the compounds.…”

Section: Resultsmentioning

confidence: 99%

“…N ‐Aryl, N ‐acyl or N ‐sulfonylisatins 4 (Figure ) can undergo ring‐opening reaction with alcohols and amines to yield the corresponding phenylglyoxamides . Recently, our research group has reported that N ‐naphthoyl‐phenylglyoxamide derivative 5 (Figure ) possessed moderate to high antibacterial activities against the common bacterial pathogens Staphylococcus aureus and Pseudomonas aeruginosa . These phenylglyoxamides can be synthesised by the ring‐opening reaction of N ‐sulfonylisatin with amines.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis and Biological Evaluation of N‐Sulfonylphenyl glyoxamide‐Based Antimicrobial Peptide Mimics as Novel Antimicrobial Agents

Nizalapur

et al. 2017

ChemistrySelect

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Antibiotic resistance is a major global health concern. There is an urgent need for the development of novel antimicrobials. Recently, phenylglyoxamide‐based small molecular antimicrobial peptide mimics have been identified as potential new leads to treat bacterial infections. Here, we describe the synthesis of novel phenylglyoxamide derivatives via the ring‐opening reaction of N‐sulfonylisatins with primary amines, followed by conversion into hydrochloride, quaternary ammonium iodide or gunidinium salts. The antibacterial activity of the compounds against Staphylococcus aureus was evaluated by in vitro assays. Structure‐activity relationship studies revealed that 5‐bromo‐substituent at the phenyl ring, octyl group appended to the ortho sulfonamide group or guanidine hydrochloride salt as the terminal group significantly contributed to potency. The most potent compound, the gunidinium salt 35 d, exhibited a minimum inhibitory concentration value of 12 μM and a therapeutic index of 15. It also demonstrated its potential to act as antimicrobial pore‐forming agent. Overall, the results identified 35 d as a new lead antimicrobial compound.

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“…Our research group has recently synthesized short glyoxamide-based peptidomimetics via the ring-opening reaction of Nnaphthoylisatins with amines and amino acids [34,35]. As part of an ongoing program to develop short antimicrobial peptidomimetics, we were interested in utilizing the biphenyl backbone due to its frequent presence in medicinal chemistry [36,37].…”

Section: Introductionmentioning

confidence: 99%

Design and synthesis of short amphiphilic cationic peptidomimetics based on biphenyl backbone as antibacterial agents

Kuppusamy

Yasir²,

Berry

et al. 2018

European Journal of Medicinal Chemistry

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Antimicrobial peptides (AMPs) and their synthetic mimics have received recent interest as new alternatives to traditional antibiotics in attempts to overcome the rise of antibiotic resistance in many microbes. AMPs are part of the natural defenses of most living organisms and they also have a unique mechanism of action against bacteria. Herein, a new series of short amphiphilic cationic peptidomimetics were synthesized by incorporating the 3'-amino-[1,1'-biphenyl]-3-carboxylic acid backbone to mimic the essential properties of natural AMPs. By altering hydrophobicity and charge, we identified the most potent analogue 25g that was active against both Gram-positive Staphylococcus aureus (MIC = 15.6 μM) and Gram-negative Escherichia coli (MIC = 7.8 μM) bacteria. Cytoplasmic permeability assay results revealed that 25g acts primarily by depolarization of lipids in cytoplasmic membranes. The active compounds were also investigated for their cytotoxicity to human cells, lysis of lipid bilayers using tethered bilayer lipid membranes (tBLMs) and their activity against established biofilms of S. aureus and E. coli.

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Synthesis and biological evaluation of N-naphthoyl-phenylglyoxamide-based small molecular antimicrobial peptide mimics as novel antimicrobial agents and biofilm inhibitors

Cited by 27 publications

References 46 publications

An examination of microcystin-LR accumulation and toxicity using tethered bilayer lipid membranes (tBLMs)

An examination of microcystin-LR accumulation and toxicity using tethered bilayer lipid membranes (tBLMs)

Design, Synthesis and Biological Evaluation of N‐Sulfonylphenyl glyoxamide‐Based Antimicrobial Peptide Mimics as Novel Antimicrobial Agents

Design and synthesis of short amphiphilic cationic peptidomimetics based on biphenyl backbone as antibacterial agents

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