Pyrazole derived ultra-short antimicrobial peptidomimetics with potent anti-biofilm activity

Ahn, Mok-Ryeon; Gunasekaran, P.; Rajasekaran, Ganesan; Kim, Eun Young; Lee, Soo-Jae; Bang, Geul; Cho, Kun; Hyun, Jaekyung; Lee, Hyunju; Jeon, Young Ho; Kim, Nam‐Hyung; Ryu, Eung K.; Shin, Song Yub; Bang, Jeong Kyu

doi:10.1016/j.ejmech.2016.09.071

Cited by 64 publications

(50 citation statements)

References 51 publications

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“…Notably the concepts of the molecular shape and the SMART models have allowed the design of novel peptide and non-peptidic mimetics of AMPs with high antimicrobial efficiency that are cationic or amphipathic and partition into the interface without filling the hydrophobic volume to the same extent such as short peptides (Oyston et al 2009;Schweizer 2009;Hadley and Hancock 2010;Kindrachuk and Napper 2010;Liu et al 2010;Mangoni and Shai 2011;Chou et al 2016;Ahn et al 2017), foldamers (Porter et al 2002;Patch and Barron 2003;Kuroda and DeGrado 2005;Violette et al 2006;Makovitzki et al 2008;…”

Section: Au7mentioning

confidence: 99%

The Mechanisms of Action of Cationic Antimicrobial Peptides Refined by Novel Concepts from Biophysical Investigations

Aisenbrey¹,

Marquette²,

Bechinger³

2019

Advances in Experimental Medicine and Biology

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Even 30 years after the discovery of magainins, biophysical and structural investigations on how these peptides interact with membranes can still bear surprises and add new interesting detail to how these peptides exert their antimicrobial action. Early on, using oriented solid-state NMR spectroscopy, it was found that the amphipathic helices formed by magainins are active when being oriented parallel to the membrane surface. More recent investigations indicate that this in-planar alignment is also found when PGLa and magainin in combination exert synergistic pore-forming activities, where studies on the mechanism of synergistic interaction are ongoing. In a related manner, the investigation of dimeric antimicrobial peptide sequences has become an interesting topic of research which bears promise to refine our views how antimicrobial action occurs. The molecular shape concept has been introduced to explain the effects of lipids and peptides on membrane morphology, locally and globally, and in particular of cationic amphipathic helices that partition into the membrane interface. This concept has been extended in this review to include more recent ideas on soft membranes that can adapt to external stimuli including membrane-disruptive molecules. In this manner, the lipids can change their shape in the presence of low peptide concentrations, thereby maintaining the bilayer properties. At higher peptide concentrations, phase transitions occur which lead to the formation of pores and membrane lytic processes. In the context of the molecular shape concept, the properties of lipopeptides, including surfactins, are shortly presented, and comparisons with the hydrophobic alamethicin sequence are made. Keywords (separated by "-") Magainin-PGLa-Cecropin-LL37-Surfacting alamethicin-Membrane topology-Membrane pore-Membrane macroscopic phase-SMART model-Carpet model-Toroidal pore-Peptide-lipid interactions-Molecular shape concept

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Section: Au7mentioning

confidence: 99%

The Mechanisms of Action of Cationic Antimicrobial Peptides Refined by Novel Concepts from Biophysical Investigations

Aisenbrey¹,

Marquette²,

Bechinger³

2019

Advances in Experimental Medicine and Biology

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“…In fact, many synthetic antibacterial peptidomimetics are currently undergoing clinical trials, including the membrane-disrupting compound LTX-109, the cationic steroid compound CSA-13, and the novel peptidomimetic brilacidin (see https://clinicaltrials.gov/ ). Recently, short peptidomimetics made of Arg and N-alkyl/aryl pyrazole residues were shown to have good antimicrobial and anti-inflammatory activities, increased proteolytic stability against trypsin digestion, and antimicrobial activity, even in the presence of physiological salts (Ahn et al, 2017 ). Another series of AMP mimetics were synthesized by incorporating a 3′-amino-[1,1′-biphenyl]-3-carboxylic acid backbone in MSI-78, a peptide currently in Phase-III clinical trials (Kuppusamy et al, 2018 ).…”

Section: Peptidomimetics Are An Improvement Over Natural Peptidesmentioning

confidence: 99%

Promising Antibiofilm Activity of Peptidomimetics

et al. 2018

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Pathogenic biofilms are a global health care concern, as they can cause extensive antibiotic resistance, morbidity, mortality, and thereby substantial economic loss. Scientific efforts have been made over the past few decades, but so far there is no effective treatment targeting the bacteria in biofilms. Antimicrobial peptidomimetics have been proposed as promising potential anti-biofilm agents. Indeed, these structurally enhanced molecules can mimic the action of peptides but are not susceptible to proteolysis or immunogenicity, the characteristic limitations of natural peptides. Here, we provide insights into antibiofilm peptidomimetic strategies and molecular targets, and discuss the design of two major peptidomimetics classes: AApeptides (N-acylated-N-aminoethyl-substituted peptides) and peptoids (N-substituted glycine units). In particular, we present details of their structural diversity and discuss the possible improvements that can be implemented in order to develop antibiofilm drug alternatives.

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“…Despite the availability of several antibiotics and chemotherapeutic agents, the treatment of pathogenic microbial infections remains a major challenge in the global healthcare ,. The emerging of multi‐drug resistant (MDR) superbugs, due to the excessive use of antimicrobials in conjunction with naturally occurring mutations in pathogenic strains have reduced the number of available antimicrobials which are being in use for the treatment. This lacuna in therapeutically active antimicrobials is escalating the need for developing alternative drug candidates on an urgent scale .…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, In Vitro Evaluation and Docking Studies of Pyrazole‐Thiazole Hybrids as Antimicrobial and Antibiofilm Agents

et al. 2018

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In the present study, a series of novel pyrazole‐thiazole hybrids (4a‐l) were designed, synthesized and assessed for their in vitro antimicrobial activity against both Gram‐positive and Gram‐negative pathogenic bacterial and fungal strains. Compounds derived from p‐CH3 phenyl (4b), p‐Br phenyl (4g), 8‐bromocoumarinyl (4k), and 6,8‐dibromocoumarinyl (4l) exhibited promising inhibitory activity against the tested bacterial strains with minimum inhibitory concentration (MIC)/minimum bactericidal concentration (MBC) spectrum of 1.9/7.8 μg/mL to 3.9/7.8 μg/mL. The compounds with p‐CH3 phenyl (4b), p‐OCH3 phenyl (4c), benzo[f]coumarinyl (4j), 8‐bromocoumarinyl (4k) substitutions showed their inhibitory potency against various Candida strains with MIC/minimum fungicidal concentration (MFC) values of 3.9/7.8 μg/mL. Also, anti‐biofilm and toxicity profile of the compounds was also tested. The biofilm inhibition results revealed that the compound 4 j exhibited promising activity with an IC50 value of 11.8 μM against S. aureus MTCC 96, while 4 k showed significant activity against S. aureus MLS16 MTCC 2940, K. planticola MTCC 530 and C. albicans MTCC 3017 with IC50 values of 12, 14 and 16 μM, respectively. The present study has emphasized that thiazole‐pyrazole hybrids with benzothiazole and coumarin scaffolds can be a novel and potent class of molecules with potential biological activities.

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Pyrazole derived ultra-short antimicrobial peptidomimetics with potent anti-biofilm activity

Cited by 64 publications

References 51 publications

The Mechanisms of Action of Cationic Antimicrobial Peptides Refined by Novel Concepts from Biophysical Investigations

The Mechanisms of Action of Cationic Antimicrobial Peptides Refined by Novel Concepts from Biophysical Investigations

Promising Antibiofilm Activity of Peptidomimetics

Design, Synthesis, In Vitro Evaluation and Docking Studies of Pyrazole‐Thiazole Hybrids as Antimicrobial and Antibiofilm Agents

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