Antimicrobial Peptides against Multidrug-Resistant Pseudomonas aeruginosa Biofilm from Cystic Fibrosis Patients

Daniel Ben Hur; Gal Kapach; Naiem Ahmad Wani; Edo Kiper; Moshe Ashkenazi; Gill Smollan; Natan Keller; Ori Efrati; Yechiel Shai

doi:10.1021/acs.jmedchem.2c00270

Antimicrobial Peptides against Multidrug-Resistant Pseudomonas aeruginosa Biofilm from Cystic Fibrosis Patients

Daniel Ben Hur, Gal Kapach, Naiem Ahmad Wani, Edo Kiper, Moshe Ashkenazi, Gill Smollan, Natan Keller, Ori Efrati, Yechiel Shai

Research output: Contribution to journal › Article › peer-review

31 Scopus citations

Abstract

Lung infection is the leading cause of morbidity and mortality in cystic fibrosis (CF) patients and is mainly dominated by Pseudomonas aeruginosa. Treatment of CF-associated lung infections is problematic because the drugs are vulnerable to multidrug-resistant pathogens, many of which are major biofilm producers like P. aeruginosa. Antimicrobial peptides (AMPs) are essential components in all life forms and exhibit antimicrobial activity. Here we investigated a series of AMPs (d,l-K6L9), each composed of six lysines and nine leucines but differing in their sequence composed of l- and d-amino acids. The d,l-K6L9 peptides showed antimicrobial and antibiofilm activities against P. aeruginosa from CF patients. Furthermore, the data revealed that the d,l-K6L9 peptides are stable and resistant to degradation by CF sputum proteases and maintain their activity in a CF sputum environment. Additionally, the d,l-K6L9 peptides do not induce bacterial resistance. Overall, these findings should assist in the future development of alternative treatments against resistant bacterial biofilms.

Original language	English
Pages (from-to)	9050-9062
Number of pages	13
Journal	Journal of Medicinal Chemistry
Volume	65
Issue number	13
DOIs	https://doi.org/10.1021/acs.jmedchem.2c00270
State	Published - 14 Jul 2022
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2022 American Chemical Society.

Funding

We would like to thank Veikhman Lyudmila, Alla Falkovich and Guy Shmul for mass spectrometry analysis, Vladimir Kiss and Melanie Bokstad Horev for technical assistance with the confocal imaging and Dr. Reinat Nevo for help with image analysis. We also thank Dr. Yoel A. Klug, Dr. Etai Rotem, Batya Zarmi and Alon Nudelman for technical assistance and insightful discussions. I thank Shani Ben Hur for her support, attention, and long weekends we spent together in the lab while I continued working on the project. The Israeli Ministry of Science and Technology (Application 3-14316) and the Israel Science Foundation (Application 1944/20) supported this work.

Funders	Funder number
Israel Science Foundation	1944/20
Ministry of science and technology, Israel	3-14316

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10.1021/acs.jmedchem.2c00270

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title = "Antimicrobial Peptides against Multidrug-Resistant Pseudomonas aeruginosa Biofilm from Cystic Fibrosis Patients",

abstract = "Lung infection is the leading cause of morbidity and mortality in cystic fibrosis (CF) patients and is mainly dominated by Pseudomonas aeruginosa. Treatment of CF-associated lung infections is problematic because the drugs are vulnerable to multidrug-resistant pathogens, many of which are major biofilm producers like P. aeruginosa. Antimicrobial peptides (AMPs) are essential components in all life forms and exhibit antimicrobial activity. Here we investigated a series of AMPs (d,l-K6L9), each composed of six lysines and nine leucines but differing in their sequence composed of l- and d-amino acids. The d,l-K6L9 peptides showed antimicrobial and antibiofilm activities against P. aeruginosa from CF patients. Furthermore, the data revealed that the d,l-K6L9 peptides are stable and resistant to degradation by CF sputum proteases and maintain their activity in a CF sputum environment. Additionally, the d,l-K6L9 peptides do not induce bacterial resistance. Overall, these findings should assist in the future development of alternative treatments against resistant bacterial biofilms.",

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AU - Wani, Naiem Ahmad

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AU - Ashkenazi, Moshe

AU - Smollan, Gill

AU - Keller, Natan

AU - Efrati, Ori

AU - Shai, Yechiel

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AB - Lung infection is the leading cause of morbidity and mortality in cystic fibrosis (CF) patients and is mainly dominated by Pseudomonas aeruginosa. Treatment of CF-associated lung infections is problematic because the drugs are vulnerable to multidrug-resistant pathogens, many of which are major biofilm producers like P. aeruginosa. Antimicrobial peptides (AMPs) are essential components in all life forms and exhibit antimicrobial activity. Here we investigated a series of AMPs (d,l-K6L9), each composed of six lysines and nine leucines but differing in their sequence composed of l- and d-amino acids. The d,l-K6L9 peptides showed antimicrobial and antibiofilm activities against P. aeruginosa from CF patients. Furthermore, the data revealed that the d,l-K6L9 peptides are stable and resistant to degradation by CF sputum proteases and maintain their activity in a CF sputum environment. Additionally, the d,l-K6L9 peptides do not induce bacterial resistance. Overall, these findings should assist in the future development of alternative treatments against resistant bacterial biofilms.

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Antimicrobial Peptides against Multidrug-Resistant Pseudomonas aeruginosa Biofilm from Cystic Fibrosis Patients

Abstract

Bibliographical note

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