Article
Bacterial response to membrane-active peptide antibiotics
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Published: | October 2, 2014 |
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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.
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