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Mar 26, 2014

Looking for More Thrust, Less Parry in Small Peptide Interactions with Bacteria

Looking for More Thrust, Less Parry in Small Peptide Interactions with Bacteria

A Ruhr-Universität Bochum (RUB) researcher in search of new antibiotics uses protein analyses to gain insights into the mechanisms of action of potential drugs. [© RUBIN, photo: Nelle]

  • With the rise in multidrug-resistant bacteria, the search for antibiotic drugs has acquired greater urgency, prompting scientists to take a closer look at antimicrobial peptides. Now, one group of scientists at Ruhr-Universität Bochum (RUB) has uncovered details of how certain small peptides interact with the outer membranes of bacteria. Not only have the scientists revealed the mode of action of a representative small peptide, they have exposed a mechanism bacteria use to defend themselves.

    The scientists hope that by improving our understanding of peptides’ mode of action and bacterial survival strategies, their work will open up new approaches for devising peptide-based antibacterial strategies. Time, they suggest, is of the essence. According to Professor Julia Bandow, Ph.D., who heads RUB’s Junior Research Group Microbial Antibiotic Research, “It is quite possible that, in 10 years’ time, all of the currently marketed antibiotics will lose their power because bacteria will have become resistant against all active agents.”

    Dr. Bandow’s team has shown, via proteome and Western blot analyses, that peptide integration into the bacterial membrane causes delocalization of essential peripheral membrane proteins. This delocalization impacts on two cellular processes, namely respiration and cell-wall biosynthesis, limiting cellular energy and undermining cell-wall integrity.

    The scientists at RUB have also described a bacterial survival strategy. After the scientists found that exogenous glutamate increases tolerance to the peptide, they realized that osmotic destabilization contributes to antibacterial efficacy. With this in mind, they were primed to notice that their test organism, Bacillus subtilis, responds to peptide stress by releasing osmoprotective amino acids, in part via mechanosensitive channels. This response, the researchers determined, is triggered by membrane-targeting bacteriolytic peptides of different structural classes as well as by hypoosmotic conditions.

    These findings were presented March 24 in the Proceedings of the National Academy of Sciences, in an article entitled, “Small cationic antimicrobial peptides delocalize peripheral membrane proteins.” This article describes the RUB group’s work with the MP196 peptide, a representative of a group of very small positively charged peptides that consist of some 4 to 10 amino acids. Earlier studies had shown that MP196 is efficient against various bacteria, including particularly problematic multiresistant pathogens that frequently cause sepsis. The mode of action, however, remained obscure.

    Now that the mode of action—a particular kind of delocalization—is better understood, researchers look forward to developing more effective antimicrobial peptides (AMPs). For example, researchers may choose to focus on developing more selective AMPs. To do so, researchers may exploit how MP196’s interaction with the cell membrane was dependent on the fatty acids present in the membrane. Since the membrane composition varies not only between human and bacterial cells, but also between different classes of bacteria, AMPs that home in on distinctive membrane structures could be developed.

    “By delocalizing crucial membrane proteins, MP196 disrupts a number of cellular processes that take place at the membrane,” said Dr. Bandow. “As a result, the development of resistance against the peptide seems particularly difficult.” The researchers are confident that MP196 can serve as a scaffold to develop drugs that attack certain classes of bacteria without damaging human cells.



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