Opposing Effects of PhoPQ and PmrAB on the Properties of Salmonella enterica serovar Typhimurium: Implications on Resistance to Antimicrobial Peptides

Tal Shprung, Naiem Ahmad Wani, Miriam Wilmes, Maria Luisa Mangoni, Arkadi Bitler, Eyal Shimoni, Hans Georg Sahl, Yechiel Shai

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

The increasing number of resistant bacteria is a major threat worldwide, leading to the search for new antibiotic agents. One of the leading strategies is the use of antimicrobial peptides (AMPs), cationic and hydrophobic innate immune defense peptides. A major target of AMPs is the bacterial membrane. Notably, accumulating data suggest that AMPs can activate the two-component systems (TCSs) of Gram-negative bacteria. These include PhoP-PhoQ (PhoPQ) and PmrA-PmrB (PmrAB), responsible for remodeling of the bacterial cell surface. To better understand this mechanism, we utilized bacteria deficient either in one system alone or in both and biophysical tools including fluorescence spectroscopy, single-cell atomic force microscopy, electron microscopy, and mass spectrometry (Moskowitz, S. M.;et al. Antimicrob. Agents Chemother. 2012, 56, 1019-1030; Cheng, H. Y.;et al. J. Biomed. Sci. 2010, 17, 60). Our data suggested that the two systems have opposing effects on the properties of Salmonella enterica. The knockout of PhoPQ made the bacteria more susceptible to AMPs by making the surface less rigid, more polarized, and permeable with a slightly more negatively charged cell wall. In addition, the periplasmic space is thinner. In contrast, the knockout of PmrAB did not affect its susceptibility, while it made the bacterial outer layer very rigid, less polarized, and less permeable than the other two mutants, with a negatively charged cell wall similar to the WT. Overall, the data suggest that the coexistence of systems with opposing effects on the biophysical properties of the bacteria contribute to their membrane flexibility, which, on the one hand, is important to accommodate changing environments and, on the other hand, may inhibit the development of meaningful resistance to AMPs.

Original languageEnglish
Pages (from-to)2943-2955
Number of pages13
JournalBiochemistry
Volume60
Issue number39
DOIs
StatePublished - 5 Oct 2021
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported in part by fundings from the German-Israel Foundation (GIF) no. 1015-264.2/2008 (to H.-G.S. and Y.S.) and the European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 278998 (to Y.S.). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Y.S. is the incumbent of the Harold S. and Harriet B. Brady Professorial Chair in Cancer Research.

Publisher Copyright:
© 2021 American Chemical Society.

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