scholarly journals Secretion, Maturation, and Activity of a Quorum Sensing Peptide (GSP) Inducing Bacteriocin Transcription in Streptococcus gallolyticus

mBio ◽  
2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Anthony Harrington ◽  
Alexis Proutière ◽  
Ryan W. Mull ◽  
Laurence du Merle ◽  
Shaynoor Dramsi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Quorum Sensing ◽  
Opportunistic Pathogen ◽  
Structure Activity Relationship ◽  
Activity Relationship ◽  
Supporting Evidence ◽  
Content Type ◽  
Link Type ◽  
Streptococcus Gallolyticus ◽  
Structure Activity

ABSTRACT Streptococcus gallolyticus subsp. gallolyticus is an emerging opportunistic pathogen responsible for septicemia and endocarditis in the elderly. Invasive infections by S. gallolyticus subsp. gallolyticus are strongly linked to the occurrence of colorectal cancer (CRC). It was previously shown that increased secondary bile salts under CRC conditions enhance the bactericidal activity of gallocin, a bacteriocin produced by S. gallolyticus subsp. gallolyticus, enabling it to colonize the mouse colon by outcompeting resident enterococci (L. Aymeric, F. Donnadieu, C. Mulet, L. du Merle, et al., Proc Natl Acad Sci U S A 115:E283–E291, 2018, https://doi.org/10.1073/pnas.1715112115). In a separate study, we showed that S. gallolyticus subsp. gallolyticus produces and secretes a 21-mer peptide that activates bacteriocin production (A. Proutière, L. du Merle, B. Périchon, H. Varet, et al., mBio 11:e03187-20, 2020, https://doi.org/10.1128/mBio.03187-20). This peptide was named CSP because of its sequence similarity with competence-stimulating peptides found in other streptococci. Here, we demonstrate that CSP is a bona fide quorum sensing peptide involved in activation of gallocin gene transcription. We therefore refer to CSP as GSP (gallocin-stimulating peptide). GSP displays some unique features, since its N-terminal amino acid lies three residues after the double glycine leader sequence. Here, we set out to investigate the processing and export pathway that leads to mature GSP. Heterologous expression in Lactococcus lactis of the genes encoding GSP and the BlpAB transporter is sufficient to produce the 21-mer form of GSP in the supernatant, indicating that S. gallolyticus subsp. gallolyticus BlpAB displays an atypical cleavage site. We also conducted the first comprehensive structure-activity relationship (SAR) analysis of S. gallolyticus subsp. gallolyticus GSP to identify its key structural features and found that unlike many other similar streptococci signaling peptides (such as CSPs), nearly half of the mature GSP sequence can be removed (residues 1 to 9) without significantly impacting the peptide activity. IMPORTANCE Streptococcus gallolyticus subsp. gallolyticus is an opportunistic pathogen associated with colorectal cancer (CRC) and endocarditis. S. gallolyticus subsp. gallolyticus utilizes quorum sensing (QS) to regulate the production of a bacteriocin (gallocin) and gain a selective advantage in colonizing the colon. In this article, we report (i) the first structure-activity relationship study of the S. gallolyticus subsp. gallolyticus QS pheromone that regulates gallocin production, (ii) evidence that the active QS pheromone is processed to its mature form by a unique ABC transporter and not processed by an extracellular protease, and (iii) supporting evidence of interspecies interactions between streptococcal pheromones. Our results revealed the minimal pheromone scaffold needed for gallocin activation and uncovered unique interactions between two streptococcal QS signals that warrant further study.

scholarly journals Secretion, maturation and activity of a quorum-sensing peptide (GSP) inducing bacteriocins transcription in Streptococcus gallolyticus

2020 ◽  
Author(s):  
Anthony Harrington ◽  
Alexis Proutiere ◽  
Shaynoor Dramsi ◽  
Yftah Tal-Gan
Keyword(s):  
Colorectal Cancer ◽  
Quorum Sensing ◽  
Sequence Similarity ◽  
The Elderly ◽  
Opportunistic Pathogen ◽  
Selective Advantage ◽  
Structural Features ◽  
Supporting Evidence ◽  
Interspecies Interactions ◽  
Streptococcus Gallolyticus

AbstractStreptococcus gallolyticus subsp. gallolyticus (Sgg) is an emerging opportunistic pathogen responsible for septicemia and endocarditis in the elderly. Invasive infections by Sgg are strongly linked to the occurrence of colorectal cancer (CRC). It was previously shown that increased secondary bile salts in CRC-conditions enhances the bactericidal activity of gallocin, a bacteriocin produced by Sgg, enabling it to colonize the mouse colon by outcompeting resident enterococci. In a separate study, we have shown that Sgg produces and secretes a 21-mer peptide that activates bacteriocin production. This peptide was named CSP because of its sequence similarity with competence stimulating peptides found in other streptococci. Here we demonstrate that CSP is a bona fide quorum-sensing peptide involved in activation of gallocin gene transcription. We therefore refer to CSP as GSP (gallocin stimulating peptide). GSP displays some unique features since its N-terminal amino-acid lies three residues after the double glycine leader sequence. Herein, we set out to investigate the processing and export pathway that leads to mature GSP. We also conducted the first comprehensive structure-activity relationship (SAR) of Sgg GSP to identify its key structural features.SignificanceStreptococcus gallolyticus subsp. gallolyticus (Sgg) is an opportunistic pathogen associated with colorectal cancer (CRC) and endocarditis. Sgg utilizes quorum-sensing (QS) to regulate the production of a bacteriocin (gallocin) and gain selective advantage in colonizing the colon. In this manuscript, we report 1) the first structure-activty relationship study of the Sgg QS pheromone that regulates gallocin production; 2) evidence that the active QS pheromone is processed to its mature form by a unique ABC transporter and not processed by an extracellular protease; and 3) supporting evidence of interspecies interactions between streptococci pheromones. Our results revealed the minimal pheromone scaffold needed for gallocin activation and uncovered unique interactions between two streptococci species QS signals that warrant further studies.

scholarly journals Identification ofStreptococcus gallolyticussubsp.gallolyticus(Biotype I) Competence-Stimulating Peptide Pheromone

2018 ◽  
Vol 200 (14) ◽  
Author(s):  
Anthony Harrington ◽  
Yftah Tal-Gan
Keyword(s):  
Colorectal Cancer ◽  
Infective Endocarditis ◽  
Quorum Sensing ◽  
Opportunistic Pathogen ◽  
Regulatory Role ◽  
Human Pathogen ◽  
Content Type ◽  
Regulatory Pathways ◽  
Streptococcus Gallolyticus ◽  
Peptide Pheromone

ABSTRACTStreptococcus gallolyticussubsp.gallolyticus, a member of the group D streptococci, is normally found in the bovine rumen and human gut. It is an opportunistic pathogen that was recently determined to be a bacterial driver of colorectal cancer, in addition to causing other diseases, such as infective endocarditis, bacteremia, neonatal meningitis, and septicemia. As an emerging pathogen, not much is known about this bacterium, its virulence mechanisms, or its virulence regulatory pathways. Previous studies suggest thatS. gallolyticussubsp.gallolyticususes a ComRS pathway, one of manyStreptococcusquorum-sensing circuitries, for competence. However, thus far, the ubiquitous ComABCDE pathway has not been studied, nor has its regulatory role inS. gallolyticussubsp.gallolyticus. We therefore sought to study theS. gallolyticussubsp.gallolyticusComABCDE quorum-sensing pathway and have identified its peptide pheromone, which is termed the competence-stimulating peptide (CSP). We further determined that this peptide regulates the production of bacteriocin-like inhibitory substances (BLISs), a phenotype that has been linked with the ComABCDE pathway in bothStreptococcus pneumoniaeandStreptococcus mutans. Our data show thatS. gallolyticussubsp.gallolyticusTX20005 produces a 21-mer CSP signal, which differs from CSP signals of otherStreptococcusspecies in that its active form begins three residues after the double-glycine leader signal of the ComC precursor peptide. Additionally, our data suggest that this peptide might not be related to competence induction, as opposed to CSP signaling peptides in otherStreptococcusspecies. This study provides the first evidence thatS. gallolyticussubsp.gallolyticusutilizes quorum sensing to eliminate competitors, presenting a potential pathway to target this emerging human pathogen.IMPORTANCEStreptococcus gallolyticussubsp.gallolyticusis an emerging human pathogen known as a causative agent of infective endocarditis, and recently, of colorectal cancer. In this work, we revealed a functional quorum-sensing circuitry inS. gallolyticussubsp.gallolyticus, including the identification of the central signaling peptide pheromone, competence-stimulating peptide (CSP), and the regulatory role of this circuitry in the production of bacteriocin-like inhibitory substances (BLISs). This work uncovered a mechanism by which this bacterium outcompetes other bacterial species and thus provides a potential tool to study this opportunistic pathogen.

scholarly journals A Computational Approach to Drug Discovery: Search for Chalcone Analogues as the Potential Candidates for Anti Colorectal Cancer (HT29)

2018 ◽  
Vol 17 (2) ◽  
pp. 64-74
Author(s):  
Neni FRIMAYANTI ◽  
Ihsan IKHTIARUDIN ◽  
Rahma DONA ◽  
Tiara Tri AGUSTINI ◽  
Fri MURDIYA ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Molecular Dynamic ◽  
Predictive Ability ◽  
3D Qsar ◽  
Quantitative Structure Activity Relationship ◽  
Structure Activity Relationship ◽  
Activity Relationship ◽  
Quantitative Structure ◽  
Data Set ◽  
Structure Activity

A series of 46 chalcone derivative compounds with their inhibitory activity against colorectal cancer were used as data set for developing the quantitative structure activity relationship (QSAR). 2D QSAR and 3D QSAR models have been developed with high predictive ability with r2 and r2(CV) of 0.81 and 0.78, respectively. Results from the 2D and 3D quantitative structure activity relationship models indicate that electrostatic parameter enhanced bioactivity of the chalcone derivatives. Further, docking and molecular dynamic simulation was performed using 2wft PDB ID as the molecular target of colon cancer. Based on the docking, molecular dynamic, and biological assay, it is confirmed that compound 2, cpd 4, cpd 21, cpd 23, cpd 27, cpd 32, cpd 38, and cpd 39 show better activity (active) against colorectal cancer cells.

scholarly journals Structure-Activity Relationship Study of the Plant-Derived Decapeptide OSIP108 Inhibiting Candida albicans Biofilm Formation

2014 ◽  
Vol 58 (8) ◽  
pp. 4974-4977 ◽  
Author(s):  
Nicolas Delattin ◽  
Katrijn De Brucker ◽  
David J. Craik ◽  
Olivier Cheneval ◽  
Barbara De Coninck ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Biofilm Formation ◽  
Structure Activity Relationship ◽  
Activity Relationship ◽  
Antibiofilm Activity ◽  
Content Type ◽  
Charged Amino Acids ◽  
Structure Activity ◽  
Relationship Study ◽  
Positively Charged

ABSTRACTWe performed a structure-activity relationship study of the antibiofilm plant-derived decapeptide OSIP108. Introduction of positively charged amino acids R, H, and K resulted in an up-to-5-fold-increased antibiofilm activity againstCandida albicanscompared to native OSIP108, whereas replacement of R9 resulted in complete abolishment of its antibiofilm activity. By combining the most promising amino acid substitutions, we found that the double-substituted OSIP108 analogue Q6R/G7K had an 8-fold-increased antibiofilm activity.

scholarly journals Combinatorial quorum sensing in Pseudomonas aeruginosa allows for novel cheating strategies

Microbiology ◽  
2020 ◽  
Vol 166 (8) ◽  
pp. 777-784 ◽  
Author(s):  
James Gurney ◽  
Sheyda Azimi ◽  
Sam P. Brown ◽  
Stephen P. Diggle
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Quorum Sensing ◽  
Type Species ◽  
Natural Populations ◽  
Opportunistic Pathogen ◽  
Growth Media ◽  
Public And Private ◽  
Content Type ◽  
Private Goods ◽  
Link Type

In the opportunistic pathogen Pseudomonas aeruginosa, quorum sensing (QS) is a social trait that is exploitable by non-cooperating cheats. Previously it has been shown that by linking QS to the production of both public and private goods, cheats can be prevented from invading populations of cooperators and this was described by Dandekar et al. (Science 2012;338:264–266) as ‘a metabolic incentive to cooperate’. We hypothesized that P. aeruginosa could evolve novel cheating strategies to circumvent private goods metabolism by rewiring its combinatorial response to two QS signals (3O-C12-HSL and C4-HSL). We performed a selection experiment that cycled P. aeruginosa between public and private goods growth media and evolved an isolate that rewired its control of cooperative protease expression from a synergistic (AND-gate) response to dual-signal input to a 3O-C12-HSL-only response. We show that this isolate circumvents metabolic incentives to cooperate and acts as a combinatorial signalling cheat, with higher fitness in competition with its ancestor. Our results show three important principles: first, combinatorial QS allows for diverse social strategies to emerge; second, restrictions levied by private goods are not sufficient to explain the maintenance of cooperation in natural populations; and third, modifying combinatorial QS responses could result in important physiological outcomes in bacterial populations.

scholarly journals Proteomic Signature of Fatty Acid Biosynthesis Inhibition Available for In Vivo Mechanism-of-Action Studies

2011 ◽  
Vol 55 (6) ◽  
pp. 2590-2596 ◽  
Author(s):  
Michaela Wenzel ◽  
Malay Patra ◽  
Dirk Albrecht ◽  
David Y.-K. Chen ◽  
K. C. Nicolaou ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Biosynthesis ◽  
Structure Activity Relationship ◽  
Mechanisms Of Action ◽  
Activity Relationship ◽  
Antibacterial Drug ◽  
Acid Biosynthesis ◽  
Content Type ◽  
Structure Activity

ABSTRACTFatty acid biosynthesis is a promising novel antibiotic target. Two inhibitors of fatty acid biosynthesis, platencin and platensimycin, were recently discovered and their molecular targets identified. Numerous structure-activity relationship studies for both platencin and platensimycin are currently being undertaken. We established a proteomic signature for fatty acid biosynthesis inhibition inBacillus subtilisusing platencin, platensimycin, cerulenin, and triclosan. The induced proteins, FabHA, FabHB, FabF, FabI, PlsX, and PanB, are enzymes involved in fatty acid biosynthesis and thus linked directly to the target pathway. The proteomic signature can now be used to assess thein vivomechanisms of action of compounds derived from structure-activity relationship programs, as demonstrated for the platensimycin-inspired chromium bioorganometallic PM47. It will further serve as a reference signature for structurally novel natural and synthetic antimicrobial compounds with unknown mechanisms of action. In summary, we described a proteomic signature inB. subtilisconsisting of six upregulated proteins that is diagnostic of fatty acid biosynthesis inhibition and thus can be applied to advance antibacterial drug discovery programs.

scholarly journals 4-Aminoquinolines Active against Chloroquine-Resistant Plasmodium falciparum: Basis of Antiparasite Activity and Quantitative Structure-Activity Relationship Analyses

2011 ◽  
Vol 55 (5) ◽  
pp. 2233-2244 ◽  
Author(s):  
Simon J. Hocart ◽  
Huayin Liu ◽  
Haiyan Deng ◽  
Dibyendu De ◽  
Frances M. Krogstad ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Quantitative Structure Activity Relationship ◽  
Structure Activity Relationship ◽  
Structural Features ◽  
Activity Relationship ◽  
Side Chain ◽  
Quantitative Structure ◽  
Content Type ◽  
Structure Activity ◽  
Contour Plots

ABSTRACTChloroquine (CQ) is a safe and economical 4-aminoquinoline (AQ) antimalarial. However, its value has been severely compromised by the increasing prevalence of CQ resistance. This study examined 108 AQs, including 68 newly synthesized compounds. Of these 108 AQs, 32 (30%) were active only against CQ-susceptiblePlasmodium falciparumstrains and 59 (55%) were active against both CQ-susceptible and CQ-resistantP. falciparumstrains (50% inhibitory concentrations [IC50s], ≤25 nM). All AQs active against both CQ-susceptible and CQ-resistantP. falciparumstrains shared four structural features: (i) an AQ ring without alkyl substitution, (ii) a halogen at position 7 (Cl, Br, or I but not F), (iii) a protonatable nitrogen at position 1, and (iv) a second protonatable nitrogen at the end of the side chain distal from the point of attachment to the AQ ring via the nitrogen at position 4. For activity against CQ-resistant parasites, side chain lengths of ≤3 or ≥10 carbons were necessary but not sufficient; they were identified as essential factors by visual comparison of 2-dimensional (2-D) structures in relation to the antiparasite activities of the AQs and were confirmed by computer-based 3-D comparisons and differential contour plots of activity againstP. falciparum. The advantage of the method reported here (refinement of quantitative structure-activity relationship [QSAR] descriptors by random assignment of compounds to multiple training and test sets) is that it retains QSAR descriptors according to their abilities to predict the activities of unknown test compounds rather than according to how well they fit the activities of the compounds in the training sets.

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