Synthetic antibacterial discovery of symbah-1, a macrocyclic β-hairpin peptide antibiotic

Randall, Justin R.; Davidson, Gillian; Fleeman, Renee; Acosta, Santos A.; Riddington, Ian M.; Cole, T. Jeffrey; DuPai, Cory D.; Davies, Bryan William

doi:10.1016/j.isci.2021.103611

Cited by 10 publications

(27 citation statements)

References 56 publications

(51 reference statements)

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“…This is highly uncommon for peptides in aqueous solution. Most require a target interaction to form a β hairpin or other secondary structure ( 23 , 24 ).…”

Section: Resultsmentioning

confidence: 99%

“…Last, we questioned whether the naïve peptide sequences discovered through our screen could be optimized to improve their potency, so we generated a 27-peptide optimization library around our most potent peptide (SySA-5) using previously described design principles ( 24 ). Most variants showed fourfold or greater potency against a multidrug-resistant strain of Acinetobacter baumannii with little or no increased toxicity (table S3).…”

Section: Resultsmentioning

confidence: 99%

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Designing and identifying β-hairpin peptide macrocycles with antibiotic potential

et al. 2023

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Peptide macrocycles are a rapidly emerging class of therapeutic, yet the design of their structure and activity remains challenging. This is especially true for those with β-hairpin structure due to weak folding properties and a propensity for aggregation. Here, we use proteomic analysis and common antimicrobial features to design a large peptide library with macrocyclic β-hairpin structure. Using an activity-driven high-throughput screen, we identify dozens of peptides killing bacteria through selective membrane disruption and analyze their biochemical features via machine learning. Active peptides contain a unique constrained structure and are highly enriched for cationic charge with arginine in their turn region. Our results provide a synthetic strategy for structured macrocyclic peptide design and discovery while also elucidating characteristics important for β-hairpin antimicrobial peptide activity.

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“…This is highly uncommon for peptides in aqueous solution. Most require a target interaction to form a β hairpin or other secondary structure ( 23 , 24 ).…”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Designing and identifying β-hairpin peptide macrocycles with antibiotic potential

et al. 2023

Self Cite

View full text Add to dashboard Cite

show abstract

“…This is highly uncommon for peptides in aqueous solution. Most require a target interaction to form a β-hairpin or other secondary structure ( 24 , 25 ).…”

Section: Resultsmentioning

confidence: 99%

“…Natural antibacterial peptides, including β-AMPs, generally require membrane or membrane mimics like lipopolysaccharide (LPS) to form alpha helical or β-hairpin secondary structures ( 24 , 25 ). For example, our natural β-hairpin peptide controls have a single molar ellipticity minimum at 200 nm in phosphate buffer alone, consistent with a random coil secondary structure (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Results from our biochemical characterization suggest high charge is important. Previous data from optimization of another SLAY identified β-AMP found that shorter peptide length and additional disulfide bonds increased potency (25). For these reasons we generated a 27-peptide optimization library around our most potent peptide (SySA-5) by shortening its length, increasing its charge, and adding the potential for a second intramolecular disulfide bond while also maintaining alternating residue side chain properties in the antiparallel β-sheets (table S1).…”

Section: Sysa Peptides Selectively Disrupt Bacterial Membranesmentioning

confidence: 99%

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Designing β-hairpin peptide macrocycles for antibiotic potential

Randall

DuPai

Cole

et al. 2022

Preprint

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Peptide macrocycles are a rapidly emerging new class of therapeutic, yet the design of their structure and activity remains challenging. This is especially true for those with β-hairpin structure due to weak folding properties and a propensity for aggregation. Here we use proteomic analysis and common antimicrobial features to design a large peptide library with macrocyclic β-hairpin structure. Using an activity-driven high-throughput screen we identify dozens of peptides killing bacteria through selective membrane disruption and analyze their biochemical features via machine learning. Active peptides contain a unique constrained structure and are highly enriched for cationic charge with arginine in their turn region. Our results provide a synthetic strategy for structured macrocyclic peptide design and discovery, while also elucidating characteristics important for β-hairpin antimicrobial peptide activity.

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Beta‐lactam resistance and the effectiveness of antimicrobial peptides against KPC‐producing bacteria

Souza

Roque‐Borda

Pavan

2022

Drug Development Research

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Bacterial resistance is a problem that is giving serious cause for concern because bacterial strains such as Acinetobacter baumannii and Pseudomonas aeruginosa are difficult to treat and highly opportunistic. These bacteria easily acquire resistance genes even from other species, which confers greater persistence and tolerance towards conventional antibiotics. These bacteria have the highest death rate in hospitalized intensive care patients, so strong measures must be taken. In this review, we focus on the use of antimicrobial peptides (AMPs) as an alternative to traditional drugs, due to their rapid action and lower risk of generating resistance by microorganisms. We also present an overview of beta-lactams and explicitly explain the activity of AMPs against carbapenemase-producing bacteria as potential alternative agents for infection control.

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Synthetic antibacterial discovery of symbah-1, a macrocyclic β-hairpin peptide antibiotic

Cited by 10 publications

References 56 publications

Designing and identifying β-hairpin peptide macrocycles with antibiotic potential

Designing and identifying β-hairpin peptide macrocycles with antibiotic potential

Designing β-hairpin peptide macrocycles for antibiotic potential

Beta‐lactam resistance and the effectiveness of antimicrobial peptides against KPC‐producing bacteria

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