Biology subjects

Gless, B. H.

Publications and source records attributed to Gless, B. H..

3 recordsLinked to original sources

bioRxiv2025

Mapping of Quorum Sensing Landscape of Commensal and Pathogenic Staphylococci Reveals a Largely Inhibitory Interaction Network

Staphylococci utilize secreted autoinducing peptides (AIPs) to regulate group behaviour through a process called quorum sensing (QS). For staphylococcal pathogens such as S. aureus, QS regulates expression of major virulence factors and QS inhibition has been proposed as an alternative to antibiotics for treatment of infections with methicillin resistant S. aureus (MRSA). Here, we surveyed the interaction map between QS systems of the pathogens Staphylococcus aureus, Staphylococcus epidermidis, and Staphylococcus lugdunensis and the 36 currently known AIPs from 22 staphylococcal species. We identified seven of these ribosomally synthesized and post-translationally modified peptides (RiPPs) in this study and all synthetic peptides were assessed for their ability to modulate QS. The mapped interactions of >280 native QS pairings were divided into human- and animal-associated staphylococci showing substantial differences in inhibitory potencies between the groups. In particular, AIPs of the bovine-associated species S. simulans displayed potential as QS inhibitors in the strains investigated in this study and were therefore chosen as starting point for a structure-activity relationship study. This study provides insights into the requirements for QS interference, yielding the most potent inhibitors reported to date for S. epidermidis and S. lugdunensis. Further, we tested an S. simulans AIP as anti-virulence agent in an assay to assess risk of acquired suppression of the inhibitory effect, and we established an assay set-up to successfully monitor agr deactivation of virulent MRSA by the QS inhibitor. Finally, a peptide was shown to attenuate skin infection caused by MRSA in a mouse model. Our results reveal a complex network of staphylococcal interactions and provide further impetus for the development of therapeutic strategies, based on QS modulation to target antibiotic-resistant pathogens. TOC Graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=103 SRC="FIGDIR/small/635662v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@f2be0aorg.highwire.dtl.DTLVardef@9aa0c2org.highwire.dtl.DTLVardef@1b02c26org.highwire.dtl.DTLVardef@12273a7_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2023

Development of Stabilized Peptide Analogues to Study a Short-lived Peptide Signal that Regulates Cell-to-Cell Communication in Listeria monocytogenes

Quorum sensing (QS) is a mechanism that regulates group behavior in bacteria, and in Gram-positive bacteria, the communication molecules are often cyclic peptides, called autoinducing peptides (AIPs). We recently showed that pentameric thiolactone-containing AIPs from Listeria monocytogenes, and from other species, spontaneously undergo rapid rearrangement to homodetic cyclopeptides, which hampers our ability to study the activity of these short-lived compounds. Here, we developed chemically modified analogues that closely mimic the native AIPs while remaining structurally intact, by introducing N-methylation or thioester-to-thioether substitutions. The stablilized AIP analogues exhibit strong QS agonism in L. monocytogenes and allow structure-activity relationships to be studied. Our data provide evidence that loudly suggest that the most potent AIP is in fact the very short-lived thiolactone-containing pentamer. Further, we find that the QS system in L. monocytogenes is more promiscuous with respect to the structural diversity allowed for agonistic AIPs than reported for the more extensively studied QS systems in Staphylococcus aureus and Staphylococcus epidermidis. The developed compounds will be important for uncovering the biology of L. monocytogenes, and the design principles should be broadly applicable to the study of AIPs in other species.

microbiology↗

bioRxiv2021

Chemical phylogenetics of the staphylococcal quorum sensing landscape

Staphylococci utilize secreted autoinducing peptides (AIPs) to regulate group behaviour through a process called quorum sensing (QS). Here, we survey the QS interaction landscape within the Staphylococcus genus by assembling a unique compound collection, comprising all the currently known AIPs. These ribosomally synthesized and posttranslationally modified peptides (RiPPs) were obtained by chemical synthesis and mapping of their ability to modulate QS was evaluated using reporter strains of common human and animal colonizing pathogens (S. aureus, S. epidermidis, S. lugdunensis). The resulting map of >200 native QS interactions provides a holistic view of nodes that contribute to the complex signalling network within the Staphylococcus genus. This overview reveals surprising cross-species QS induction and identify the first pan-inhibitory AIP, which is then shown to attenuate MRSA induced skin infection in a mouse model. Our results expose a complex universe of possible staphylococcal interactions and provide further impetus for development of therapeutics based on QS modulators targeting antibiotic resistant pathogens.

microbiology↗