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      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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          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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          Author and article information

          Journal
          Res. Microbiol.
          Research in microbiology
          Elsevier BV
          1769-7123
          0923-2508
          October 27 2015
          : 167
          : 2
          Affiliations
          [1 ] Department of Systems Biology, Matematiktorvet, Technical University of Denmark, 2800 Kgs Lyngby, Denmark. Electronic address: lincit@bio.dtu.dk.
          [2 ] Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address: henrik.franzyk@sund.ku.dk.
          [3 ] Thrombosis Research, University of Southern Denmark, Odense, Denmark. Electronic address: ypalarasah@health.sdu.dk.
          [4 ] Research Unit of Clinical Microbiology, University of Southern Denmark, Odense, Denmark. Electronic address: thandersen@health.sdu.dk.
          [5 ] DTU CEN, Fysikvej, Center for Electron Nanoscopy, Technical University of Denmark, 2800 Kgs Lyngby, Denmark. Electronic address: ramona.mateiu@cen.dtu.dk.
          [6 ] Department of Systems Biology, Matematiktorvet, Technical University of Denmark, 2800 Kgs Lyngby, Denmark. Electronic address: gram@bio.dtu.dk.
          Article
          S0923-2508(15)00166-7
          10.1016/j.resmic.2015.10.002
          26499211
          cdd4d4d2-2877-4042-b8f6-b52867fee96b
          History

          Antibiotics,Antimicrobial peptide,Peptidomimetics,Plasma,Synergy

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