Using a cell-cell communication process called quorum sensing (QS), certain bacteria can coordinate their gene expression by monitoring the production of a chemical signal, which acts as a proxy for the local population density. Many Gram-positive bacteria utilize the accessory gene regulator (agr) QS system in which the chemical signal is a small cyclic peptide known as the auto-inducing peptide (AIP). Listeria monocytogenes (Lm), an important food-borne pathogen, uses the agr system to regulate a variety of virulence phenotypes related to infection, biofilm formation, and survival in soil environments. While the agr system has been relatively well studied in other Gram-positive pathogens, including Staphylococcus aureus, there remains much to learn about how the agr system functions in Lm. Efficacious chemical agonists and antagonists of the Lm agr system would be powerful tools for probing the specific role of agr in the infection cycle, cell-to-cell spread, and persistence of Lm in a laboratory setting, as well as for developing methods to combat this pathogen in both healthcare and industrial settings. To this end, we used the native Lm AIP as a scaffold to develop a collection of synthetic AIP mimics to modulate agr activity in Lm. First, a series of analogs were synthesized to probe the contribution of each amino acid in the native AIP to agr activity using newly constructed agr GFP reporter strains in Lm. The structure-activity relationships gathered from these studies guided the design of new peptide analogs with significantly increased activities and potencies, culminating in the development of 1) Lm QS agonists with increased potency relative to the native AIP and 2) Lm QS antagonists capable of reducing agr activity down to basal levels. Most notably, these analogs were effective at modulating biofilm formation in Lm, with the lead antagonist able to reduce wild-type biofilm formation by over 90%. This study represents a critical first step in understanding how chemical methods can be deployed to regulate QS and concomitant virulence outcomes in Lm.

Structure-function analysis of the native quorum sensing peptide of Listeria monocytogenes reveals a route toward inhibition

ACS Spring Meeting 2021

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