An alternatingly amphiphilic, resistance-resistant antimicrobial oligoguanidine with dual mechanisms of action

Chen, Zhiyong; Zhou, Chao; Xu, Yangfan; Wen, Kang; Song, Junfeng; Bai, Silei; Wu, Chenxuan; Huang, Wei; Cai, Qingyun; Zhou, Kai; Wang, Hui; Wang, Yingjie; Feng, Xinxin; Bai, Yugang

doi:10.1016/j.biomaterials.2021.120858

Cited by 31 publications

(51 citation statements)

References 56 publications

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“…[3,4] A low-cost and easily scalable synthesis of SMAMPs, in comparison to AMPs, make this class of membrane-lytic agents a good subject for further broad studies on the structure-activity relationship (SAR). [5] Despite a high antimicrobial efficiency, low hemolytic activity and low cytotoxicity, of some already investigated SMAMPs and AMPs, [6][7][8][9][10] their practical use is still limited to topical applications. [10,11] For example, highly active polyhexamethylene guanidines (PHMG) and polyhexamethylene biguanides (PHMB) are employed as disinfectants and antiseptics for various applications (e.g., Kerlix AMD for wound care).…”

Section: Introductionmentioning

confidence: 99%

“…To date, many different SMAMPs such as polyacrylates, [15][16][17][18] polynorbornenes, [19][20][21][22] polycarbonates, [23,24] poly-𝛽-lactams (nylon-3), [25][26][27] poly(styrene-alt-maleic anhydride) derivatives, [28][29][30][31] and ionenes [6][7][8][32][33][34][35][36][37][38][39][40][41][42] (polycations containing cationic group inside the mainchain) have been synthesized and investigated as antimicrobial agents. Published data has revealed that a hydrophilic-lipophilic balance (HLB) is one of the most important factors determining selectivity toward microbes over red blood cells (RBCs) as highlighted in many reviews.…”

Section: Introductionmentioning

confidence: 99%

“…[45] Interestingly, many reported ionenes, of which HLB is moved strongly toward hydrophilicity, are highly active against bacteria and almost no hemolytic. [6][7][8]32,[34][35][36][37][38][39][40][41] Besides AMPs produced by microorganisms, there is a large group of AMPs called host-defense peptides (HDPs), which are an important element of the innate immune system of all multicellular organisms. [46] Interestingly, besides cationic and hydrophobic groups present in a majority of reported SMAMPs, HDPs contain additional neutral, hydrophilic moieties.…”

Section: Introductionmentioning

confidence: 99%

“…Despite a high antimicrobial efficiency, low hemolytic activity and low cytotoxicity, of some already investigated SMAMPs and AMPs, [ 6–10 ] their practical use is still limited to topical applications. [ 10,11 ] For example, highly active polyhexamethylene guanidines (PHMG) and polyhexamethylene biguanides (PHMB) are employed as disinfectants and antiseptics for various applications (e.g., Kerlix AMD for wound care).…”

Section: Introductionmentioning

confidence: 99%

“…[ 45 ] Interestingly, many reported ionenes, of which HLB is moved strongly toward hydrophilicity, are highly active against bacteria and almost no hemolytic. [ 6–8,32,34–41 ]…”

Section: Introductionmentioning

confidence: 99%

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Influence of PEG Subunit on the Biological Activity of Ionenes: Synthesis of Novel Polycations, Antimicrobial and Toxicity Studies

Kopiasz

Kulbacka

Drężek

et al. 2022

Macromolecular Bioscience

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An alarming increase of antibiotic resistance among pathogens creates an urgent need to develop new antimicrobial agents. Many reported polycations show high antimicrobial activity along with low hemolytic activity. Unfortunately, most of those molecules remain highly cytotoxic against various mammalian cells. In this work, a systematic study on the impact of triethylene glycol monomethyl ether side groups (short polyethylene glycol (PEG) analog) on antimicrobial, hemolytic, and cytotoxic properties of novel amphiphilic ionenes is presented. A detailed description of synthesis, leading to well‐defined alternating polymers, which differ in structural elements responsible for hydrophilicity (PEG) and hydrophobicity (alkyl chain), is presented. Obtained results show that the PEG moiety and fine‐tuned hydrophilic‐lipophilic balance of ionenes synergistically lead to low cytotoxic, low hemolytic molecules with high activity against S. aureus, including methicillin‐resistant strains (MRSA). Additionally, the results of mechanistic studies on bacterial cells and fluorescently labeled liposomes are also discussed.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…[ 45 ] Interestingly, many reported ionenes, of which HLB is moved strongly toward hydrophilicity, are highly active against bacteria and almost no hemolytic. [ 6–8,32,34–41 ]…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Influence of PEG Subunit on the Biological Activity of Ionenes: Synthesis of Novel Polycations, Antimicrobial and Toxicity Studies

Kopiasz

Kulbacka

Drężek

et al. 2022

Macromolecular Bioscience

View full text Add to dashboard Cite

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Expand and Sensitize: Guanidine‐Functionalized Exopolysaccharide Nanoparticles Cause Bacterial Cell Expansion and Antibiotic Sensitization

Li,

Jia,

Seidi

et al. 2023

Adv Funct Materials

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Conventional antibacterial agents and mechanisms are frequently observed to be ineffective due to the evolution of bacteria to the strains with stronger antibiotic resistance, and hence developing alternative antibacterial materials and mechanisms is urgently needed. Here, guanidine‐functionalized exopolysaccharide (EPS) nanoparticles (termed EPGNs) with durable antibacterial and antibiofilm activities are developed. Very interestingly, the EPGNs obtained by the reaction of EPS, epichlorohydrin, and polyhexamethylene guanidine hydrochloride exhibit an unconventional antibacterial mechanism, i.e., they can induce substantial bacterial cell expansion by upregulating the SulA and DicB proteins that are responsible for cell division inhibition, along with the increase of reactive oxygen species production, bacterial cell surface disruption, and bacterial ribosomal RNA degradation. The transcriptome analysis reveals that EPGNs can hinder cell motility, induce loss of cell integrity, decrease the resistance of bacteria to oxidative stress, and finally lead to cell death. Moreover, EPGNs can effectively accelerate the bacteria‐infected wound healing. This work provides the first example that nanomaterials can cause bacterial cell expansion by affecting intracellular structures and inhibiting cell division, and it may inspire other researchers to investigate the effect of antibacterial materials on the change of bacterial volume and design unconventional antibacterial materials/strategies.

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Improving the Hemocompatibility of Antimicrobial Peptidomimetics through Amphiphilicity Masking Using a Secondary Amphiphilic Polymer

Chen

Zhou

Wang

et al. 2022

Adv Healthcare Materials

Self Cite

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Antimicrobial peptidomimetics (AMPMs) have received widespread attention as potentially powerful weapons against antibiotic resistance. However, AMPMs' membrane disruption mechanism not only brings resistance-resistant nature, but also nonspecific binding and disruption toward eukaryotic cell membranes, and consequently, their hemolytic activity is the primary concern on clinical applications. Here, the preparation and screening of an AMPM library is reported, through which a best-performing hit, PT-b1, can be obtained. To further improve PT-b1's hemocompatibility, a strategy is devised to mask the amphiphilicity of the AMPM using a charge-free, FDA-approved amphiphilic polymer, Pluronic F-127 (PF127). A PF127 solution containing PT-b1 can form a temperature-sensitive, absorbable hydrogel at higher concentration, but dissolve and complex with PT-b1 through hydrophobic interactions at lower concentration or lower temperature. The complexation from PF127 can mask the amphiphilicity of PT-b1 and render it extremely hemocompatible, yet the reversibility in such nanocomplexation and the existence of a secondary mechanism of action ensure that the AMPM's potency remains unchanged. The in vivo effectiveness of this antimicrobial hydrogel system is demonstrated using a mice wound infection model established with Methicillin-resistant Staphylococcus aureus, and observations indicate the hydrogel can promote wound healing and suppress bacteria-caused inflammation even when resistant pathogens are involved.

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An alternatingly amphiphilic, resistance-resistant antimicrobial oligoguanidine with dual mechanisms of action

Cited by 31 publications

References 56 publications

Influence of PEG Subunit on the Biological Activity of Ionenes: Synthesis of Novel Polycations, Antimicrobial and Toxicity Studies

Influence of PEG Subunit on the Biological Activity of Ionenes: Synthesis of Novel Polycations, Antimicrobial and Toxicity Studies

Expand and Sensitize: Guanidine‐Functionalized Exopolysaccharide Nanoparticles Cause Bacterial Cell Expansion and Antibiotic Sensitization

Improving the Hemocompatibility of Antimicrobial Peptidomimetics through Amphiphilicity Masking Using a Secondary Amphiphilic Polymer

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