Improved in vitro evaluation of novel antimicrobials: potential synergy between human plasma and antibacterial peptidomimetics, AMPs and antibiotics against human pathogenic bacteria
Stable peptidomimetics mimicking natural antimicrobial peptides (AMPs) have emerged as a promising class of potential novel antibiotics. In the present study, we aimed at determining whether the antibacterial activity of two α-peptide/β-peptoid peptidomimetics against a range of bacterial pathogens...
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Published in | Research in microbiology Vol. 167; no. 2; pp. 72 - 82 |
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Main Authors | , , , , , |
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Language | English |
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01.02.2016
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Abstract | Stable peptidomimetics mimicking natural antimicrobial peptides (AMPs) have emerged as a promising class of potential novel antibiotics. In the present study, we aimed at determining whether the antibacterial activity of two α-peptide/β-peptoid peptidomimetics against a range of bacterial pathogens was affected by conditions mimicking in vivo settings. Their activity was enhanced to an unexpected degree in the presence of human blood plasma for thirteen pathogenic Gram-positive and Gram-negative bacteria. MIC values typically decreased 2- to 16-fold in the presence of a human plasma concentration that alone did not damage the cell membrane. Hence, MIC and MBC data collected in these settings appear to represent a more appropriate basis for in vivo experiments preceding clinical trials. In fact, concentrations of peptidomimetics and peptide antibiotics (e.g. polymyxin B) required for in vivo treatments might be lower than traditionally deduced from MICs determined in laboratory media. Thus, antibiotics previously considered too toxic could be developed into usable last-resort drugs, due to ensuing lowered risk of side effects. In contrast, the activity of the compounds was significantly decreased in heat-inactivated plasma. We hypothesize that synergistic interactions with complement proteins and/or clotting factors most likely are involved. |
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AbstractList | Stable peptidomimetics mimicking natural antimicrobial peptides (AMPs) have emerged as a promising class of potential novel antibiotics. In the present study, we aimed at determining whether the antibacterial activity of two α-peptide/β-peptoid peptidomimetics against a range of bacterial pathogens was affected by conditions mimicking in vivo settings. Their activity was enhanced to an unexpected degree in the presence of human blood plasma for thirteen pathogenic Gram-positive and Gram-negative bacteria. MIC values typically decreased 2- to 16-fold in the presence of a human plasma concentration that alone did not damage the cell membrane. Hence, MIC and MBC data collected in these settings appear to represent a more appropriate basis for in vivo experiments preceding clinical trials. In fact, concentrations of peptidomimetics and peptide antibiotics (e.g. polymyxin B) required for in vivo treatments might be lower than traditionally deduced from MICs determined in laboratory media. Thus, antibiotics previously considered too toxic could be developed into usable last-resort drugs, due to ensuing lowered risk of side effects. In contrast, the activity of the compounds was significantly decreased in heat-inactivated plasma. We hypothesize that synergistic interactions with complement proteins and/or clotting factors most likely are involved. Stable peptidomimetics mimicking natural antimicrobial peptides (AMPs) have emerged as a promising class of potential novel antibiotics. In the present study, we aimed at determining whether the antibacterial activity of two alpha -peptide/ beta -peptoid peptidomimetics against a range of bacterial pathogens was affected by conditions mimicking in vivo settings. Their activity was enhanced to an unexpected degree in the presence of human blood plasma for thirteen pathogenic Gram-positive and Gram-negative bacteria. MIC values typically decreased 2- to 16-fold in the presence of a human plasma concentration that alone did not damage the cell membrane. Hence, MIC and MBC data collected in these settings appear to represent a more appropriate basis for in vivo experiments preceding clinical trials. In fact, concentrations of peptidomimetics and peptide antibiotics (e.g. polymyxin B) required for in vivo treatments might be lower than traditionally deduced from MICs determined in laboratory media. Thus, antibiotics previously considered too toxic could be developed into usable last-resort drugs, due to ensuing lowered risk of side effects. In contrast, the activity of the compounds was significantly decreased in heat-inactivated plasma. We hypothesize that synergistic interactions with complement proteins and/or clotting factors most likely are involved. |
Author | Gram, Lone Andersen, Thomas Emil Palarasah, Yaseelan Citterio, Linda Franzyk, Henrik Mateiu, Ramona Valentina |
Author_xml | – sequence: 1 givenname: Linda surname: Citterio fullname: Citterio, Linda email: lincit@bio.dtu.dk organization: Department of Systems Biology, Matematiktorvet, Technical University of Denmark, 2800 Kgs Lyngby, Denmark – sequence: 2 givenname: Henrik surname: Franzyk fullname: Franzyk, Henrik email: henrik.franzyk@sund.ku.dk organization: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark – sequence: 3 givenname: Yaseelan surname: Palarasah fullname: Palarasah, Yaseelan email: ypalarasah@health.sdu.dk organization: Thrombosis Research, University of Southern Denmark, Odense, Denmark – sequence: 4 givenname: Thomas Emil surname: Andersen fullname: Andersen, Thomas Emil email: thandersen@health.sdu.dk organization: Research Unit of Clinical Microbiology, University of Southern Denmark, Odense, Denmark – sequence: 5 givenname: Ramona Valentina surname: Mateiu fullname: Mateiu, Ramona Valentina email: ramona.mateiu@cen.dtu.dk organization: DTU CEN, Fysikvej, Center for Electron Nanoscopy, Technical University of Denmark, 2800 Kgs Lyngby, Denmark – sequence: 6 givenname: Lone surname: Gram fullname: Gram, Lone email: gram@bio.dtu.dk organization: Department of Systems Biology, Matematiktorvet, Technical University of Denmark, 2800 Kgs Lyngby, Denmark |
BackLink | https://www.ncbi.nlm.nih.gov/pubmed/26499211$$D View this record in MEDLINE/PubMed |
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Snippet | Stable peptidomimetics mimicking natural antimicrobial peptides (AMPs) have emerged as a promising class of potential novel antibiotics. In the present study,... |
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SubjectTerms | Adenosine Monophosphate - metabolism Anti-Bacterial Agents - metabolism Antibiotics Antimicrobial peptide Bacteria Bacteria - drug effects Drug Synergism Humans Microbial Sensitivity Tests Microbial Viability - drug effects Peptidomimetics Peptidomimetics - metabolism Plasma Plasma - metabolism Synergy |
Title | Improved in vitro evaluation of novel antimicrobials: potential synergy between human plasma and antibacterial peptidomimetics, AMPs and antibiotics against human pathogenic bacteria |
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