The PhoQ-Activating Potential of Antimicrobial Peptides Contributes to Antimicrobial Efficacy and Is Predictive of the Induction of Bacterial Resistance

Kindrachuk, Jason; Paur, Nicole; Reiman, Carla; Scruten, Erin; Napper, Scott

doi:10.1128/aac.00854-07

Cited by 14 publications

(13 citation statements)

References 46 publications

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“…These systems respond to diverse environmental signals, such as pH (Gao and Lynn, 2005), small molecules (Kaspar et al, 1999; Lee et al, 1999), ions (García Véscovi et al, 1996), and peptides (Kindrachuk et al, 2007), and regulate critical responses, such as ion transport and virulence (Miller et al, 1989). A prototypical two-component system includes a transmembrane (TM) histidine kinase (HK) receptor and a cytoplasmic response regulator (Mascher et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Cys-Scanning Disulfide Crosslinking and Bayesian Modeling Probe the Transmembrane Signaling Mechanism of the Histidine Kinase, PhoQ

et al. 2014

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Summary Bacteria transduce signals across the membrane using two-component systems (TCSs), consisting of a membrane-spanning sensor histidine kinase and a cytoplasmic response regulator. In Gram negative bacteria, the PhoPQ TCS senses cations and antimicrobial peptides, yet little is known about the structural changes involved in transmembrane signaling. We construct a model of PhoQ signal transduction using Bayesian inference, based on disulfide crosslinking data and homologous crystal structures. The data are incompatible with a single conformation but are instead consistent with two interconverting structures. These states differ in membrane depth of the periplasmic acidic patch and the reciprocal displacement of diagonal helices along the dimer interface. Studies of multiple histidine kinases suggest this repacking might be a common mode of signal transduction in sensor His-kinase receptors. Since a similar scissors model has been ruled out in CheA-linked chemoreceptors, the new evidence suggests that sensor His-kinase and CheA-linked receptors possess different signaling mechanisms.

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Section: Introductionmentioning

confidence: 99%

Cys-Scanning Disulfide Crosslinking and Bayesian Modeling Probe the Transmembrane Signaling Mechanism of the Histidine Kinase, PhoQ

et al. 2014

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“…Resistance-The likelihood that bacteria will develop resistance to AMPs by activation of PhoP-PhoQ suggests that these bacteria should be more resistant to AMPs upon preincubation with the peptides (22,33,37). We therefore determined the MICs of the peptides against WT bacteria cultivated for 20 h with subinhibitory concentrations of AMPs (0.25 MIC) (Fig.…”

Section: Short Term Preincubation Of Wt Bacteria With Amps Does Not Imentioning

confidence: 99%

Effect of PhoP-PhoQ Activation by Broad Repertoire of Antimicrobial Peptides on Bacterial Resistance

Shprung

Peleg

Rosenfeld

et al. 2012

Journal of Biological Chemistry

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Pathogenic bacteria can resist their microenvironment by changing the expression of virulence genes. In Salmonella typhimurium, some of these genes are controlled by the two-component system PhoP-PhoQ. Studies have shown that activation of the system by cationic antimicrobial peptides (AMPs) results, among other changes, in outer membrane remodeling. However, it is not fully clear what characteristics of AMPs are required to activate the PhoP-PhoQ system and whether activation can induce resistance to the various AMPs. For that purpose, we investigated the ability of a broad repertoire of AMPs to traverse the inner membrane, to activate the PhoP-PhoQ system, and to induce bacterial resistance. The AMPs differ in length, composition, and net positive charge, and the tested bacteria include two wild-type (WT) Salmonella strains and their corresponding PhoP-PhoQ knock-out mutants. A lacZ-reporting system was adapted to follow PhoP-PhoQ activation. The data revealed that: (i) a good correlation exists among the extent of the positive charge, hydrophobicity, and amphipathicity of an AMP and its potency to activate PhoP-PhoQ; (ii) a ؉1 charged peptide containing histidines was highly potent, suggesting the existence of an additional mechanism independent of the peptide charge; (iii) the WT bacteria are more resistant to AMPs that are potent activators of PhoP-PhoQ; (iv) only a subset of AMPs, independent of their potency to activate the system, is more toxic to the mutated bacteria compared with the WT strains; and (v) short term exposure of WT bacteria to these AMPs does not enhance resistance. Overall, this study advances our understanding of the molecular mechanism by which AMPs activate PhoP-PhoQ and induce bacterial resistance. It also reveals that some AMPs can overcome such a resistance mechanism.

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“…Thus, peptide optimization will benefit from consideration of the PhoQ activating potential in addition to other therapeutic activities of interest. That activation of PhoPQ is not equal for all HDPs indicates that variables of sequence and/or structure are associated with PhoQ activation potential [123]. It may therefore be possible to design peptides with reduced ability to activate PhoQ while maintaining or improving other desired characteristics.…”

Section: B Phoq Ligand Potentialmentioning

confidence: 98%

“…Peptides with reduced PhoQ-activating potential would be anticipated to have improved therapeutic potential. We have proposed a novel strategy for mathematical treatment of minimal inhibitory concentration data that permits discrimination and quantification of PhoQ activating potential ( Table 2) [123].…”

Section: B Phoq Ligand Potentialmentioning

confidence: 99%

Structure-Activity Relationships of Multifunctional Host Defence Peptides

Kindrachuk¹,

Napper

2010

MRMC

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Host defence peptides (HDPs) are multi-functional inducers and effectors of host immunity. Through their direct antimicrobial activity HDPs have for been successfully utilized for many years as topical antibiotics and food preservatives. The more recent appreciation of HDP immunomodulatory activities offers additional opportunities for application as systemic antimicrobials, anti-inflammatory agents and vaccine adjuvants. HDPs have demonstrated proof-of-principle success in each of these applications. Optimization of HDPs for these objectives will benefit from a greater comprehension of the structural basis of their various activities. Such an understanding will facilitate rational design and/or selection of peptides with enhanced properties. This is complicated, however, by the diversity of HDP sequences, structures and mechanisms of action. Furthermore, while the ability of HDPs to undergo template-driven formation of bioactive structures enables these small peptides to perform a diverse range of actions it also complicates efforts to understand contributions of particular structural features to specific activities. With recognition of these limitations, but consideration of the emerging importance of this exciting class of molecules, we review the current understanding of the structural basis of select HDP activities as well as present strategies for HDP selection and optimization.

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The PhoQ-Activating Potential of Antimicrobial Peptides Contributes to Antimicrobial Efficacy and Is Predictive of the Induction of Bacterial Resistance

Cited by 14 publications

References 46 publications

Cys-Scanning Disulfide Crosslinking and Bayesian Modeling Probe the Transmembrane Signaling Mechanism of the Histidine Kinase, PhoQ

Cys-Scanning Disulfide Crosslinking and Bayesian Modeling Probe the Transmembrane Signaling Mechanism of the Histidine Kinase, PhoQ

Effect of PhoP-PhoQ Activation by Broad Repertoire of Antimicrobial Peptides on Bacterial Resistance

Structure-Activity Relationships of Multifunctional Host Defence Peptides

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