Antimicrobial α-defensins as multi-target inhibitors against amyloid formation and microbial infection

Zhang, Yanxian; Liu, Yonglan; Tang, Yanan; Zhang, Dong; He, Huacheng; Wu, Jiang; Zheng, Jie

doi:10.1039/d1sc01133b

Cited by 30 publications

(23 citation statements)

References 102 publications

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“…It has recently been proposed that Aβ can be considered an AMP; thus, representing a type of innate immune defense protein that protects the host from a variety of pathogens [ 22 , 39 , 40 ] and that other proteins with antimicrobial activity, such as α- and β-defensins, lactoferrin, cystatins A and B, histatin 1, statherin, and thymosin β4 play a key role in AD [ 41 , 42 , 43 , 44 , 45 ].…”

Section: Introductionmentioning

confidence: 99%

Antimicrobial Peptides (AMPs) in the Pathogenesis of Alzheimer’s Disease: Implications for Diagnosis and Treatment

et al. 2022

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Alzheimer’s disease (AD) represents the most frequent type of dementia in elderly people. There are two major forms of the disease: sporadic (SAD)—whose causes are not completely understood—and familial (FAD)—with clear autosomal dominant inheritance. The two main hallmarks of AD are extracellular deposits of amyloid-beta (Aβ) peptide and intracellular deposits of the hyperphosphorylated form of the tau protein (P-tau). An ever-growing body of research supports the infectious hypothesis of sporadic forms of AD. Indeed, it has been documented that some pathogens, such as herpesviruses and certain bacterial species, are commonly present in AD patients, prompting recent clinical research to focus on the characterization of antimicrobial peptides (AMPs) in this pathology. The literature also demonstrates that Aβ can be considered itself as an AMP; thus, representing a type of innate immune defense peptide that protects the host against a variety of pathogens. Beyond Aβ, other proteins with antimicrobial activity, such as lactoferrin, defensins, cystatins, thymosin β4, LL37, histatin 1, and statherin have been shown to be involved in AD. Here, we summarized and discussed these findings and explored the diagnostic and therapeutic potential of AMPs in AD.

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Section: Introductionmentioning

confidence: 99%

Antimicrobial Peptides (AMPs) in the Pathogenesis of Alzheimer’s Disease: Implications for Diagnosis and Treatment

et al. 2022

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“…The relationship between amyloidogenic and antimicrobial properties plays an important role in the development of hybrid AMPs. Thus, it is known that amyloidogenic peptides, like antimicrobial peptides, can have a toxic effect on bacterial cells [52]. In addition, the amino acid sequences included in the spine of amyloid fibrils are sufficiently resistant to the action of proteases, which is one of the diagnostic properties of amyloid fibrils [53,54].…”

Section: Introductionmentioning

confidence: 99%

Is It Possible to Create Antimicrobial Peptides Based on the Amyloidogenic Sequence of Ribosomal S1 Protein of P. aeruginosa?

Grishin

Domnin

Кравченко

et al. 2021

IJMS

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The development and testing of new antimicrobial peptides (AMPs) represent an important milestone toward the development of new antimicrobial drugs that can inhibit the growth of pathogens and multidrug-resistant microorganisms such as Pseudomonas aeruginosa, Gram-negative bacteria. Most AMPs achieve these goals through mechanisms that disrupt the normal permeability of the cell membrane, which ultimately leads to the death of the pathogenic cell. Here, we developed a unique combination of a membrane penetrating peptide and peptides prone to amyloidogenesis to create hybrid peptide: “cell penetrating peptide + linker + amyloidogenic peptide”. We evaluated the antimicrobial effects of two peptides that were developed from sequences with different propensities for amyloid formation. Among the two hybrid peptides, one was found with antibacterial activity comparable to antibiotic gentamicin sulfate. Our peptides showed no toxicity to eukaryotic cells. In addition, we evaluated the effect on the antimicrobial properties of amino acid substitutions in the non-amyloidogenic region of peptides. We compared the results with data on the predicted secondary structure, hydrophobicity, and antimicrobial properties of the original and modified peptides. In conclusion, our study demonstrates the promise of hybrid peptides based on amyloidogenic regions of the ribosomal S1 protein for the development of new antimicrobial drugs against P. aeruginosa.

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“…Our study found that pCA induced deamidation of elongation factor Tu. These results suggest that the antibacterial action of pCA on C. sakazakii is multi-target ( Zhang et al, 2021 ). But whether C. sakazakii is easy to develop resistance to pCA needs further study.…”

Section: Discussionmentioning

confidence: 95%

Proteomic Analysis Revealed Metabolic Inhibition and Elongation Factor Tu Deamidation by p-Coumaric Acid in Cronobacter sakazakii

Lü

Xue

et al. 2022

Front. Microbiol.

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Screening drugs and compounds to fight against Cronobacter sakazakii (C. sakazakii), one of the most common pathogens that can cause fatal necrotizing enterocolitis, septicema and meningitis, is still needed. We found that p-coumaric acid (pCA) has an inhibitory effect on C. sakazakii in vitro and in vivo. Proteomic changes of C. sakazakii BAA-894 exposed to pCA were studied to reveal the antibacterial mechanisms involved. A total of 1,553 proteins were identified in C. sakazakii BAA-894 by label-free proteomics analysis. Fuzzy cluster analysis showed that 33 were up-regulated, and 110 were down-regulated with pCA treatment. Gene Ontology (GO) analysis concluded that pCA caused the change of metabolic state of bacteria and generally in the state of metabolic inhibition. KEGG Enrichment Analysis (KEGG) analysis showed that pCA inhibited energy metabolism and distorted the balance of amino acid metabolism. Posttranslational modification analysis showed that pCA affected the deamidation of three proteins, including Elongation factor Tu, one of the vital proteins in bacteria. Molecular docking suggested the hydrogen bond between the pCA carboxyl group and Elongation factor Tu Asn-64 might contribute to deamidation. Overall, we found that pCA interfered with cellular energy and amino acid metabolism and promoted elongation factor Tu deamidation, suggesting that pCA can be an effective natural substitute to control C. sakazakii.

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Antimicrobial α-defensins as multi-target inhibitors against amyloid formation and microbial infection

Abstract: Amyloid aggregation and microbial infection are considered as pathological risk factors for developing amyloid diseases, including Alzheimer’s (AD), type II diabetes (T2D), Parkinson’s diseases (PD), and medullary thyroid carcinoma (MTC)....

Cited by 30 publications

References 102 publications

Antimicrobial Peptides (AMPs) in the Pathogenesis of Alzheimer’s Disease: Implications for Diagnosis and Treatment

Antimicrobial Peptides (AMPs) in the Pathogenesis of Alzheimer’s Disease: Implications for Diagnosis and Treatment

Is It Possible to Create Antimicrobial Peptides Based on the Amyloidogenic Sequence of Ribosomal S1 Protein of P. aeruginosa?

Proteomic Analysis Revealed Metabolic Inhibition and Elongation Factor Tu Deamidation by p-Coumaric Acid in Cronobacter sakazakii

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