Design and characterization of chionodracine-derived antimicrobial peptides with enhanced activity against drug-resistant human pathogens

Olivieri, Cristina; Bugli, Francesca; Menchinelli, Giulia; Veglia, Gianluigi; Buonocore, Francesco; Scapigliati, Giuseppe; Stocchi, V.; Ceccacci, Francesca; Papi, Massimiliano; Sanguinetti, Maurizio; Porcelli, Fernando

doi:10.1039/c8ra08065h

Cited by 14 publications

(38 citation statements)

References 60 publications

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“…These results agree with the partition data previously published, showing partition constants for Cnd and Cnd mutants higher in POPC/POPG than in pure POPC [30,31].…”

Section: Secondary Structure Analysis By Circular Dichroismsupporting

confidence: 93%

“…However, these differences could be related with the different mode of action of the three peptides. In fact, Cnd and Cnd-m3 are membranolytic peptides [29,30] while Cnd-m3a can permeate through the bacteria cell membrane and directly interact with intracellular nucleic acid [31]. These results in combination with CD investigations suggest that the interaction of Cnd and Cnd-m3…”

Section: Steady-state Anisotropymentioning

confidence: 87%

“…More than 3000 AMPs are reported in public database [39] giving a good source of information to delineate strategies for the AMP design. Here, we selected the two Cnd analogues, which showed a potent antimicrobial activity against multidrug resistant bacteria and investigated their interaction with model membranes in order to gain insight on such interactions that could be useful for the rational design of novel antimicrobial agents [30,31]. These analogues were designed considering the number of positive charges, the distribution of hydrophobic residues and the location of specificity determinants.…”

Section: Discussionmentioning

confidence: 99%

“…Cnd and Cnd-m3 displayed 11 hydrophobic interactions. The thermodynamic characterization of the interaction between peptides and vesicles made 100% of POPC and of POPC/POPG (molar ratio 70:30) was carried out and the data show that both peptides display a marked preference for lipid mixtures mimicking the prokaryotic cell membranes (POPC/POPG) [30,31]. Moreover, we showed that the antimicrobial activity of Cnd-m3 with respect to Cnd increased against MDR nosocomial bacteria strains.…”

Section: Introductionmentioning

confidence: 89%

“…Moreover, we showed that the antimicrobial activity of Cnd-m3 with respect to Cnd increased against MDR nosocomial bacteria strains. For instance, we showed that the MIC decreased by two times for MRSA (Methicillin resistant Staphylococcus aureus) to 30 times for KPC (Klebsiella pneumoniae carbapenemase) [30]. The antimicrobial activity of Cnd-m3a decreased as compared to Cnd-m3, however, its selectivity ratio increased from 2.4 to 4.9 [31].…”

Section: Introductionmentioning

confidence: 96%

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Structural Analysis and Design of Chionodracine-Derived Peptides Using Circular Dichroism and Molecular Dynamics Simulations

Borocci

Pelle

Ceccacci³

et al. 2020

IJMS

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Antimicrobial peptides have been identified as one of the alternatives to the extensive use of common antibiotics as they show a broad spectrum of activity against human pathogens. Among these is Chionodracine (Cnd), a host-defense peptide isolated from the Antarctic icefish Chionodraco hamatus, which belongs to the family of Piscidins. Previously, we demonstrated that Cnd and its analogs display high antimicrobial activity against ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter species). Herein, we investigate the interactions with lipid membranes of Cnd and two analogs, Cnd-m3 and Cnd-m3a, showing enhanced potency. Using a combination of Circular Dichroism, fluorescence spectroscopy, and all-atom Molecular Dynamics (MD) simulations, we determined the structural basis for the different activity among these peptides. We show that all peptides are predominantly unstructured in water and fold, preferentially as α-helices, in the presence of lipid vesicles of various compositions. Through a series of MD simulations of 400 ns time scale, we show the effect of mutations on the structure and lipid interactions of Cnd and its analogs. By explaining the structural basis for the activity of these analogs, our findings provide structural templates to design minimalistic peptides for therapeutics.

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“…These results agree with the partition data previously published, showing partition constants for Cnd and Cnd mutants higher in POPC/POPG than in pure POPC [30,31].…”

Section: Secondary Structure Analysis By Circular Dichroismsupporting

confidence: 93%