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Infektiologie Update 2014: 24. Jahrestagung der Paul-Ehrlich-Gesellschaft für Chemotherapie (PEG)

Paul-Ehrlich-Gesellschaft für Chemotherapie (PEG)

16. - 18.10.2014, Weimar

Bacterial response to membrane-active peptide antibiotics

Meeting Abstract

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  • author Michaela Wenzel - Bacterial Cell Biology, Swammerdam Institute for Life Sciences, Universiteit van Amsterdam, Amsterdam
  • author Julia E. Bandow - Angewandte Mikrobiologie, Ruhr-Universität Bochum, Bochum

Infektiologie Update 2014. 24. Jahrestagung der Paul-Ehrlich-Gesellschaft für Chemotherapie (PEG). Weimar, 16.-18.10.2014. Düsseldorf: German Medical Science GMS Publishing House; 2014. Doc14peg21

doi: 10.3205/14peg21, urn:nbn:de:0183-14peg219

Published: October 2, 2014

© 2014 Wenzel et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc-nd/3.0/deed.en). You are free: to Share – to copy, distribute and transmit the work, provided the original author and source are credited.


Outline

Text

Increasing antibiotic resistance in hand with decreasing antibiotic approvals has founded an urgent need for novel antimicrobial agents. Antibiotics acting on the bacterial cell envelope have been highly successful in terms of inhibition of peptidoglycan crosslinking [1]. However, the cell envelope offers further interesting antibiotic targets such as membrane biogenesis and integrity.

Specific proteomic signatures for fatty acid biosynthesis inhibition, membrane damage, and inhibition of membrane-bound cell wall biosynthesis steps were established to form a basis for mode of action diagnosis of novel cell envelope-targeting antibiotics [2], [3]. The established signatures were employed in mode of action elucidation of antimicrobial peptides and organometallic peptidomimetics [4], [5], [6].

Synthetic organometallic peptide backbone derivatives constitute a completely novel class of antibiotics. Displaying excellent antibacterial activity and limited toxicity for mammalian cells, the hetero-tri-metallic compound FcPNA, containing a ferrocene, a cymantrene, and a rhenium complex, targets the cytoplasmic membrane leading to depolarization and energy limitation. The ferrocene moiety additionally caused formation of reactive oxygen species in bacterial cells [5].

The hexapeptide MP196, a small but yet typical representative of short cationic antimicrobial peptides, was chosen for in depth analysis of the mode of action of this compound class and the countermeasures bacteria employ to survive peptide stress [6]. MP196 was found to integrate into the bacterial membrane. Its antibacterial action is based on delocalization of peripheral membrane proteins like cytochrome c and MurG, resulting in inhibition of respiration and cell wall biosynthesis. Consequently, bacterial cells suffer substantial energy limitation and cell wall integrity is corrupted. Bacteria adapt to this peptide stress by adjusting their membrane and cell wall composition, up-regulation of impaired cellular processes, synthesis of membrane stabilizing proteins, and release of osmoprotective amino acids.


References

1.
Schneider T, Sahl HG. An oldie but a goodie – cell wall biosynthesis as antibiotic target pathway. Int J Med Microbiol. 2010;300:161-9. DOI: 10.1016/j.ijmm.2009.10.005 External link
2.
Wenzel M, Patra M, Albrecht D, Chen DY, Nicolaou KC, Metzler-Nolte N, Bandow JE. Proteomic signature of fatty acid biosynthesis inhibition available for in vivo mechanism-of-action studies. Antimicrob Agents Chemother. 2011;55:2590–6. DOI: 10.1128/AAC.00078-11 External link
3.
Wenzel M, Kohl B, Münch D, Raatschen N, Albada HB, Hamoen LW, Metzler-Nolte N, Sahl HG, Bandow JE. Proteomic response of Bacillus subtilis to lantibiotics reflects differences in interaction with the cytoplasmic membrane. Antimicrob Agents Chemother. 2012;56:5749–57. DOI: 10.1128/AAC.01380-12 External link
4.
Wenzel M, Patra M, Senges CH, Ott I, Stepanek JJ, Pinto A, Prochnow P, Langklotz S, Metzler-Nolte N, Bandow JE. Analysis of the mechanism of action of potent hetero-tri-organometallic compounds: a structurally new class of antibiotics. ACS Chem Biol. 2013;8:1442-50. DOI: 10.1021/cb4000844 External link
5.
Münch D, Müller A, Schneider T, Kohl B, Wenzel M, Bandow JE, Maffioli S, Sosio M, Donadio S, Wimmer R, Sahl HG. The lantibiotic NAI107 binds to bactoprenol-bound cell wall precursors and impairs membrane functions. J Biol Chem. 2014;289:12063-76. DOI: 10.1074/jbc.M113.537449 External link
6.
Wenzel M, Chiriac AI, Otto A, Zweytick D, May C, Schumacher C, Gust R, Albada HB, Penkova M, Krämer U, Erdmann R, Metzler-Nolte N, Straus SK, Bremer E, Becher D, Brötz-Oesterhelt H, Sahl HG, Bandow JE. Antimicrobial peptides delocalize peripheral membrane proteins. Proc Natl Acad Sci U S A. 2014;111:E1409-18. DOI: 10.1073/pnas.1319900111 External link