Characterization of an Autoinducing Peptide Signal Reveals Highly Efficacious Synthetic Inhibitors and Activators of Quorum Sensing and Biofilm Formation in <i>Listeria monocytogenes</i>

West, Korbin H. J.; Ma, Stella V.; Pensinger, Daniel A.; Tucholski, Trisha; Tiambeng, Timothy N.; Eisenbraun, Emma L.; Yehuda, Avishag; Hayouka, Zvi; Ge, Ying; Sauer, John-Demian; Blackwell, Helen E.

doi:10.1021/acs.biochem.3c00373

Cited by 9 publications

(2 citation statements)

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“…aureus toxin production via agr inhibition. Given the native AIP-AgrC receptor specificity that pervades agr -type QS systems, the discovery of multispecies-active compounds with the ability to block virulence phenotypes, such as the compounds introduced herein and recently reported agr modulators in Listeria monocytogenes, represents a meaningful advance for studying and attenuating QS in complex, disease-relevant contexts.…”

Section: Discussionmentioning

confidence: 99%

Synthetic Peptides Capable of Potent Multigroup Staphylococcal Quorum Sensing Activation and Inhibition in Both Cultures and Biofilm Communities

Eisenbraun,

Vulpis,

Prosser

et al. 2024

J. Am. Chem. Soc.

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The pathogen Staphylococcus epidermidis uses a chemical signaling process, i.e., quorum sensing (QS), to form robust biofilms and cause human infection. Many questions remain about QS in S. epidermidis, as it uses this intercellular communication pathway to both negatively and positively regulate virulence traits. Herein, we report synthetic multigroup agonists and antagonists of the S. epidermidis accessory gene regulator (agr) QS system capable of potent superactivation and complete inhibition, respectively. These macrocyclic peptides maintain full efficacy across the three major agr specificity groups, and their activity can be "mode-switched" from agonist to antagonist via subtle residue-specific structural changes. We describe the design and synthesis of these non-native peptides and demonstrate that they can appreciably decrease biofilm formation on abiotic surfaces, underscoring the potential for agr agonism as a route to block S. epidermidis virulence. Additionally, we show that both the S. epidermidis agonists and antagonists are active in S. aureus, another common pathogen with a related agr system, yet only as antagonists. This result not only revealed one of the most potent agr inhibitors known in S. aureus but also highlighted differences in the mechanisms of agr agonism and antagonism between these related bacteria. Finally, our investigations reveal unexpected inhibitory behavior for certain S. epidermidis agr agonists at sub-activating concentrations, an observation that can be leveraged for the design of future probes with enhanced potencies. Together, these peptides provide a powerful tool set to interrogate the role of QS in S. epidermidis infections and in Staphylococcal pathogenicity in general.

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Section: Discussionmentioning

confidence: 99%

Synthetic Peptides Capable of Potent Multigroup Staphylococcal Quorum Sensing Activation and Inhibition in Both Cultures and Biofilm Communities

Eisenbraun,

Vulpis,

Prosser

et al. 2024

J. Am. Chem. Soc.

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“…Chemical antagonists able to diminish Lm Agr activity and thus leading to the reduction of biofilm formation by over 90% were recently discovered. 114 Moreover, in silico analysis revealed different proteins secreted by lactic acid bacteria working as a promising anti-QS strategy, by inhibiting the translocation of cyclic AIP via AgrB and its recognition by the AgrC active site. 115…”

Section: Quorum Sensingmentioning

confidence: 99%