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

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          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-K 6L 9), each composed of six lysines and nine leucines but differing in their sequence composed of l- and d-amino acids. The d, l-K 6L 9 peptides showed antimicrobial and antibiofilm activities against P. aeruginosa from CF patients. Furthermore, the data revealed that the d, l-K 6L 9 peptides are stable and resistant to degradation by CF sputum proteases and maintain their activity in a CF sputum environment. Additionally, the d, l-K 6L 9 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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          Most cited references52

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          The biofilm matrix.

          The microorganisms in biofilms live in a self-produced matrix of hydrated extracellular polymeric substances (EPS) that form their immediate environment. EPS are mainly polysaccharides, proteins, nucleic acids and lipids; they provide the mechanical stability of biofilms, mediate their adhesion to surfaces and form a cohesive, three-dimensional polymer network that interconnects and transiently immobilizes biofilm cells. In addition, the biofilm matrix acts as an external digestive system by keeping extracellular enzymes close to the cells, enabling them to metabolize dissolved, colloidal and solid biopolymers. Here we describe the functions, properties and constituents of the EPS matrix that make biofilms the most successful forms of life on earth.
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            Bacterial biofilms: a common cause of persistent infections.

            Bacteria that attach to surfaces aggregate in a hydrated polymeric matrix of their own synthesis to form biofilms. Formation of these sessile communities and their inherent resistance to antimicrobial agents are at the root of many persistent and chronic bacterial infections. Studies of biofilms have revealed differentiated, structured groups of cells with community properties. Recent advances in our understanding of the genetic and molecular basis of bacterial community behavior point to therapeutic targets that may provide a means for the control of biofilm infections.
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              Antimicrobial peptides of multicellular organisms.

              Multicellular organisms live, by and large, harmoniously with microbes. The cornea of the eye of an animal is almost always free of signs of infection. The insect flourishes without lymphocytes or antibodies. A plant seed germinates successfully in the midst of soil microbes. How is this accomplished? Both animals and plants possess potent, broad-spectrum antimicrobial peptides, which they use to fend off a wide range of microbes, including bacteria, fungi, viruses and protozoa. What sorts of molecules are they? How are they employed by animals in their defence? As our need for new antibiotics becomes more pressing, could we design anti-infective drugs based on the design principles these molecules teach us?
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                Author and article information

                Journal
                J Med Chem
                J Med Chem
                jm
                jmcmar
                Journal of Medicinal Chemistry
                American Chemical Society
                0022-2623
                1520-4804
                27 June 2022
                14 July 2022
                : 65
                : 13
                : 9050-9062
                Affiliations
                []Department of Biomolecular Sciences, Weizmann Institute of Science , Rehovot 76100, Israel
                []Pediatric Pulmonary Institute and National CF Center, Edmond and Lilly Safra Children’s Hospital, Sheba Medical Center , Tel Hashomer, Ramat Gan 52621, Israel
                []Sackler Faculty of Medicine, Tel-Aviv University , Tel-Aviv 69978, Israel
                []The Department of Health Management, Ariel University , Ariel 40700, Israel
                [§ ]Microbiology Laboratories, Edmond and Lili Safra Children’s Hospital, Sheba Medical Center, Tel-Hashomer, Ariel University , Ramat Gan 52621, Israel
                Author notes
                Author information
                https://orcid.org/0000-0003-4151-5513
                Article
                10.1021/acs.jmedchem.2c00270
                9289885
                35759644
                47070b81-81f0-40cf-b057-8c47ff215d41
                © 2022 American Chemical Society

                Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained ( https://creativecommons.org/licenses/by/4.0/).

                History
                Funding
                Funded by: Ministry of Science, Technology and Space, doi 10.13039/501100001738;
                Award ID: 3-14316
                Funded by: Israel Science Foundation, doi 10.13039/501100003977;
                Award ID: 1944/20
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                jm2c00270
                jm2c00270

                Pharmaceutical chemistry
                Pharmaceutical chemistry

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