Mechanistic Landscape of Membrane-Permeabilizing Peptides

Guha, Shantanu; Ghimire, Jenisha; Wu, Eric; Wimley, William C.

doi:10.1021/acs.chemrev.8b00520

Cited by 199 publications

(214 citation statements)

References 533 publications

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“…Membrane permeabilization is the most common mechanism of antimicrobial peptide action. Researchers have proposed multiple models of peptides interacting with membranes . Based on our data, we have an interesting finding that zp3 seems to be more likely to attack the central region of the bacterial cell.…”

Section: Resultsmentioning

confidence: 63%

“…Researchersh ave proposed multiple modelso fp eptides interacting with membranes. [36,42] Based on our data, we have an interesting finding that zp3 seemst ob em ore likely to attack the central region of the bacterial cell. In STEM images, we observed clear substance accumulation at the cell poles ( Figure 8A).…”

Section: Zp3 Showshigher Affinity For the Bacterial Cell Center And Lmentioning

confidence: 60%

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Phenol‐Soluble‐Modulin‐Inspired Amphipathic Peptides Have Bactericidal Activity against Multidrug‐Resistant Bacteria

et al. 2019

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Phenol‐soluble modulins (PSMs) are a large family of cytolytic peptide toxins produced by Staphylococcus aureus. Based on their amino acid sequences, we have constructed a small library of cationic isoleucine‐rich peptides for antimicrobial evaluation. Relative to the parent PSMs, peptide zp3 (GIIAGIIIKIKK‐NH2) was found to possess greatly improved physicochemical properties (soluble in water) and antibacterial activity (MIC=8 μm for E. coli, B. subtilis, and C. freundii) while maintaining low hemolytic activity (<5 % at 256 μm) and cytotoxicity (HEK293 cells IC50>80 μm). We reasoned that the selective activity of zp3 toward bacterial cells is due to its amphiphilic nature and positive net charge. Moreover, it is difficult for bacteria to develop resistance against zp3. Through microscopic studies of E. coli, we demonstrated that zp3 can penetrate the bacterial membrane, thereby causing leakage of the bacterial cytoplasm. Our findings present a promising antimicrobial peptide lead, which has great potential for further chemical modification.

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Section: Resultsmentioning

confidence: 63%

Section: Zp3 Showshigher Affinity For the Bacterial Cell Center And Lmentioning

confidence: 60%

Phenol‐Soluble‐Modulin‐Inspired Amphipathic Peptides Have Bactericidal Activity against Multidrug‐Resistant Bacteria

et al. 2019

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“…A total of 3156 AMPs is listed in the APD, most of which were discovered in nature [13]. An analysis of 2700 of the 3156 AMPs in the APD showed that these peptides all have different structures and sequence motifs, and because they have a broad spectrum, they can kill a range of pathogens [42,43]. Interestingly, one-third of the AMPs are derived from frogs [44].…”

Section: Antimicrobial Peptide Databasementioning

confidence: 99%

“…Numerous approaches to peptide design have been introduced to make AMPs less toxic for humans while maintaining or improving their potency to eliminate bacteria [11,42], e.g., rational design [119,120], combinatorial peptide libraries [75,121], high-throughput screening [122,123], database-guided approaches [124,125], structure-function-guided design [86,126,127], and molecular dynamics simulations [44]. Three major methods to improve AMP function have been described: (i) High-throughput screening can be used to identify potential AMPs [128][129][130].…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Development and Challenges of Antimicrobial Peptides for Therapeutic Applications

2020

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More than 3000 antimicrobial peptides (AMPs) have been discovered, seven of which have been approved by the U.S. Food and Drug Administration (FDA). Now commercialized, these seven peptides have mostly been utilized for topical medications, though some have been injected into the body to treat severe bacterial infections. To understand the translational potential for AMPs, we analyzed FDA-approved drugs in the FDA drug database. We examined their physicochemical properties, secondary structures, and mechanisms of action, and compared them with the peptides in the AMP database. All FDA-approved AMPs were discovered in Gram-positive soil bacteria, and 98% of known AMPs also come from natural sources (skin secretions of frogs and toxins from different species). However, AMPs can have undesirable properties as drugs, including instability and toxicity. Thus, the design and construction of effective AMPs require an understanding of the mechanisms of known peptides and their effects on the human body. This review provides an overview to guide the development of AMPs that can potentially be used as antimicrobial drugs.

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“…4A), and putatively modulate their permeability (42) in what is known as carpet model (61). The mechanism by which such an interaction could cause a transient permeabilization is still a matter of debate, although the asymmetric distribution on the membrane bilayer has been pointed out as plausible reason (62). Further experimental work with the identified proteins could shed light on the potential transport mechanism.…”

Section: Metabolite Transportmentioning

confidence: 99%

The puzzle of metabolite exchange and identification of putative octotrico peptide repeat expression regulators in the nascent photosynthetic organelles ofPaulinella chromatophora

Oberleitner

Poschmann

Macorano

et al. 2020

Preprint

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The cercozoan amoeba Paulinella chromatophora contains photosynthetic organelles - termed chromatophores - that evolved from a cyanobacterium, independently from plastids in plants and algae. Despite the more recent origin of the chromatophore, it shows tight integration into the host cell. It imports hundreds of nucleus-encoded proteins, and diverse metabolites are exchanged across the two chromatophore envelope membranes. However, the limited set of chromatophore-encoded transporters appears insufficient for supporting metabolic connectivity or protein import. Furthermore, chromatophore-localized biosynthetic pathways as well as multiprotein complexes include proteins of dual genetic origin, suggesting coordination of gene expression levels between chromatophore and nucleus. These findings imply that similar to the situation in mitochondria and plastids, nuclear factors evolved that control metabolite exchange and gene expression in the chromatophore. Here we show by mass spectrometric analyses of enriched insoluble protein fractions that, unexpectedly, nucleus-encoded transporters are not inserted into the chromatophore inner envelope membrane. Thus, despite the apparent maintenance of its barrier function, canonical metabolite transporters are missing in this membrane. Instead we identified several expanded groups of short chromatophore-targeted orphan proteins. Members of one of these groups are characterized by a single transmembrane helix, and others contain amphipathic helices. We hypothesize that these proteins are involved in modulating membrane permeability. Furthermore, we identified an expanded family of chromatophore-targeted helical repeat proteins. These proteins show similar domain architectures as known organelle-targeted octotrico peptide repeat expression regulators in algae and plants suggesting their convergent evolution as nuclear regulators of gene expression levels in the chromatophore.ImportanceThe endosymbiotic acquisition of mitochondria and plastids >1 billion years ago was central for the evolution of eukaryotic life. However, owing to their ancient origin, these organelles provide only limited insights into the initial stages of organellogenesis. The chromatophore in Paulinella evolved ~100 million years ago and thus, offers the possibility to gain valuable insights into early stages and common rules in organelle evolution. Critical to organellogenesis appears to be the establishment of nuclear control over metabolite exchange and gene expression in the endosymbiont. Here we show that the mechanism generating metabolic connectivity of the chromatophore fundamentally differs from the one for mitochondria and plastids, but likely rather resembles the poorly understood mechanism in various bacterial endosymbionts in plants and insects. Furthermore, we describe a novel class of chromatophore-targeted helical repeat proteins which evolved convergently to plastid-targeted expression regulators and are likely involved in gene expression control in the chromatophore.

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Mechanistic Landscape of Membrane-Permeabilizing Peptides

Cited by 199 publications

References 533 publications

Phenol‐Soluble‐Modulin‐Inspired Amphipathic Peptides Have Bactericidal Activity against Multidrug‐Resistant Bacteria

Phenol‐Soluble‐Modulin‐Inspired Amphipathic Peptides Have Bactericidal Activity against Multidrug‐Resistant Bacteria

Development and Challenges of Antimicrobial Peptides for Therapeutic Applications

The puzzle of metabolite exchange and identification of putative octotrico peptide repeat expression regulators in the nascent photosynthetic organelles ofPaulinella chromatophora

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