scholarly journals Multiple and Overlapping Functions of Quorum Sensing Proteins for Cell Specialization in Bacillus Species

2020 ◽  
Vol 202 (10) ◽  
Author(s):  
Abel Verdugo-Fuentes ◽  
Gabriela Gastélum ◽  
Jorge Rocha ◽  
Mayra de la Torre
Keyword(s):  
Quorum Sensing ◽  
Bacillus Species ◽  
Bacterial Populations ◽  
Content Type ◽  
Collective Behaviors ◽  
Gram Positive Bacteria ◽  
Signaling Peptides ◽  
Moonlighting Proteins ◽  
Sporulation Initiation ◽  
Cell Specialization

ABSTRACT In bacterial populations, quorum sensing (QS) systems participate in the regulation of specialization processes and regulate collective behaviors that mediate interactions and allow survival of the species. In Gram-positive bacteria, QS systems of the RRNPP family (Rgg, Rap, NprR, PlcR, and PrgX) consist of intracellular receptors and their cognate signaling peptides. Two of these receptors, Rap and NprR, have regained attention in Bacillus subtilis and the Bacillus cereus group. Some Rap proteins, such as RapH and Rap60, are multifunctional and/or redundant in function, linking the specialization processes of sporulation and competence, as well as global expression changes in the transition phase in B. subtilis. NprR, an evolutionary intermediate between Rap and RRNPP transcriptional activators, is a bifunctional regulator that modulates sporulation initiation and activates nutrient scavenging genes. In this review, we discuss how these receptors switch between functions and connect distinct signaling pathways. Based on structural evidence, we propose that RapH and Rap60 should be considered moonlighting proteins. Additionally, we analyze an evolutionary and ecological perspective to understand the multifunctionality and functional redundancy of these regulators in both Bacillus spp. and non-Bacillus Firmicutes. Understanding the mechanistic, structural, ecological, and evolutionary basis for the multifunctionality and redundancy of these QS systems is a key step for achieving the development of innovative technologies for health and agriculture.

scholarly journals Rap Protein Paralogs of Bacillus thuringiensis: a Multifunctional and Redundant Regulatory Repertoire for the Control of Collective Functions

2019 ◽  
Vol 202 (6) ◽  
Author(s):  
Gabriela Gastélum ◽  
Mayra de la Torre ◽  
Jorge Rocha
Keyword(s):  
Bacillus Thuringiensis ◽  
Quorum Sensing ◽  
Bacillus Cereus ◽  
Proteolytic Activity ◽  
Biofilm Formation ◽  
Bacterial Populations ◽  
Content Type ◽  
Regulatory Circuits ◽  
Signaling Peptides ◽  
The Face

ABSTRACT Quorum sensing (QS) is a mechanism of synthesis and detection of signaling molecules to regulate gene expression and coordinate behaviors in bacterial populations. In Bacillus subtilis, multiple paralog Rap-Phr QS systems (receptor-signaling peptides) are highly redundant and multifunctional, interconnecting the regulation of differentiation processes such as sporulation and competence. However, their functions in the Bacillus cereus group are largely unknown. We evaluated the functions of Rap proteins in Bacillus thuringiensis Bt8741, which codes for eight Rap-Phr systems; these were individually overexpressed to study their participation in sporulation, biofilm formation, spreading, and extracellular proteolytic activity. Our results show that four Rap-Phr systems (RapC, RapK, RapF, and RapLike) inhibit sporulation, two of which (RapK and RapF) probably dephosphorylate Spo0F from the Spo0A phosphorelay; these two Rap proteins also inhibit biofilm formation. Four systems (RapC, RacF1, RacF2, and RapLike) participate in spreading inhibition; finally, six systems (RapC, -F, -F2, -I, and -I1 and RapLike) decrease extracellular proteolytic activity. We foresee that functions performed by Rap proteins of Bt8741 could also be carried out by Rap homologs in other strains within the B. cereus group. These results indicate that Rap-Phr systems constitute a highly multifunctional and redundant regulatory repertoire that enables B. thuringiensis and other species from the B. cereus group to efficiently regulate collective functions during their life cycle in the face of changing environments. IMPORTANCE The Bacillus cereus group of bacteria includes species of high economic, clinical, biological warfare, and biotechnological interest, e.g., B. anthracis in bioterrorism, B. cereus in food intoxications, and B. thuringiensis in biocontrol. Knowledge about the ecology of these bacteria is hindered by our limited understanding of the regulatory circuits that control differentiation and specialization processes. Here, we uncover the participation of eight Rap quorum-sensing receptors in collective functions of B. thuringiensis. These proteins are highly multifunctional and redundant in their functions, linking ecologically relevant processes such as sporulation, biofilm formation, spreading, extracellular proteolytic activity, and probably other functions in species from the B. cereus group.

scholarly journals The Vibrio cholerae Quorum-Sensing Protein VqmA Integrates Cell Density, Environmental, and Host-Derived Cues into the Control of Virulence

mBio ◽  
2020 ◽  
Vol 11 (4) ◽  
Author(s):  
Ameya A. Mashruwala ◽  
Bonnie L. Bassler
Keyword(s):  
Small Intestine ◽  
Quorum Sensing ◽  
Vibrio Cholerae ◽  
Cell Density ◽  
Chemical Communication ◽  
Bile Salts ◽  
Anaerobic Growth ◽  
Signal Molecules ◽  
Content Type ◽  
Collective Behaviors

ABSTRACT Quorum sensing is a chemical communication process in which bacteria use the production, release, and detection of signal molecules called autoinducers to orchestrate collective behaviors. The human pathogen Vibrio cholerae requires quorum sensing to infect the small intestine. There, V. cholerae encounters the absence of oxygen and the presence of bile salts. We show that these two stimuli differentially affect quorum-sensing function and, in turn, V. cholerae pathogenicity. First, during anaerobic growth, V. cholerae does not produce the CAI-1 autoinducer, while it continues to produce the DPO autoinducer, suggesting that CAI-1 may encode information specific to the aerobic lifestyle of V. cholerae. Second, the quorum-sensing receptor-transcription factor called VqmA, which detects the DPO autoinducer, also detects the lack of oxygen and the presence of bile salts. Detection occurs via oxygen-, bile salt-, and redox-responsive disulfide bonds that alter VqmA DNA binding activity. We propose that VqmA serves as an information processing hub that integrates quorum-sensing information, redox status, the presence or absence of oxygen, and host cues. In response to the information acquired through this mechanism, V. cholerae appropriately modulates its virulence output. IMPORTANCE Quorum sensing (QS) is a process of chemical communication that bacteria use to orchestrate collective behaviors. QS communication relies on chemical signal molecules called autoinducers. QS regulates virulence in Vibrio cholerae, the causative agent of the disease cholera. Transit into the human small intestine, the site of cholera infection, exposes V. cholerae to the host environment. In this study, we show that the combination of two stimuli encountered in the small intestine, the absence of oxygen and the presence of host-produced bile salts, impinge on V. cholerae QS function and, in turn, pathogenicity. We suggest that possessing a QS system that is responsive to multiple environmental, host, and cell density cues enables V. cholerae to fine-tune its virulence capacity in the human intestine.

scholarly journals Signal Biosynthesis Inhibition with Ambuic Acid as a Strategy To Target Antibiotic-Resistant Infections

2017 ◽  
Vol 61 (8) ◽  
Author(s):  
Daniel A. Todd ◽  
Corey P. Parlet ◽  
Heidi A. Crosby ◽  
Cheryl L. Malone ◽  
Kristopher P. Heilmann ◽  
...  
Keyword(s):  
Quorum Sensing ◽  
Bacterial Infections ◽  
Bacterial Pathogens ◽  
Gram Positive ◽  
Antibiotic Resistant ◽  
Content Type ◽  
Lead Compounds ◽  
Major Interest ◽  
Signaling Peptides

ABSTRACT There has been major interest by the scientific community in antivirulence approaches against bacterial infections. However, partly due to a lack of viable lead compounds, antivirulence therapeutics have yet to reach the clinic. Here we investigate the development of an antivirulence lead targeting quorum sensing signal biosynthesis, a process that is conserved in Gram-positive bacterial pathogens. Some preliminary studies suggest that the small molecule ambuic acid is a signal biosynthesis inhibitor. To confirm this, we constructed a methicillin-resistant Staphylococcus aureus (MRSA) strain that decouples autoinducing peptide (AIP) production from regulation and demonstrate that AIP production is inhibited in this mutant. Quantitative mass spectrometric measurements show that ambuic acid inhibits signal biosynthesis (50% inhibitory concentration [IC50] of 2.5 ± 0.1 μM) against a clinically relevant USA300 MRSA strain. Quantitative real-time PCR confirms that this compound selectively targets the quorum sensing regulon. We show that a 5-μg dose of ambuic acid reduces MRSA-induced abscess formation in a mouse model and verify its quorum sensing inhibitory activity in vivo. Finally, we employed mass spectrometry to identify or confirm the structure of quorum sensing signaling peptides in three strains each of S. aureus and Staphylococcus epidermidis and single strains of Enterococcus faecalis, Listeria monocytogenes, Staphylococcus saprophyticus, and Staphylococcus lugdunensis. By measuring AIP production by these strains, we show that ambuic acid possesses broad-spectrum efficacy against multiple Gram-positive bacterial pathogens but does not inhibit quorum sensing in some commensal bacteria. Collectively, these findings demonstrate the promise of ambuic acid as a lead for the development of antivirulence therapeutics.

scholarly journals Optimal Response to Quorum-Sensing Signals Varies in Different Host Environments with Different Pathogen Group Size

mBio ◽  
2020 ◽  
Vol 11 (3) ◽  
Author(s):  
Liqin Zhou ◽  
Leyla Slamti ◽  
Didier Lereclus ◽  
Ben Raymond
Keyword(s):  
Bacillus Thuringiensis ◽  
Quorum Sensing ◽  
Social Interactions ◽  
Group Size ◽  
Social Evolution ◽  
Local Population ◽  
Gram Positive ◽  
Competitive Fitness ◽  
Content Type ◽  
Gram Positive Bacteria

ABSTRACT The persistence of genetic variation in master regulators of gene expression, such as quorum-sensing systems, is hard to explain. Here, we investigated two alternative hypotheses for the prevalence of polymorphic quorum sensing in Gram-positive bacteria, i.e., the use of different signal/receptor pairs (‘pherotypes’) to regulate the same functions. First, social interactions between pherotypes or ‘facultative cheating’ may favor rare variants that exploit the signals of others. Second, different pherotypes may increase fitness in different environments. We evaluated these hypotheses in the invertebrate pathogen Bacillus thuringiensis, using three pherotypes expressed in a common genetic background. Facultative cheating could occur in well-mixed host homogenates provided there was minimal cross talk between competing pherotypes. However, facultative cheating did not occur when spatial structure was increased in static cultures or in naturalistic oral infections, where common pherotypes had higher fitness. There was clear support for environment-dependent fitness; pherotypes varied in responsiveness to signals and in mean competitive fitness. Notably, competitive fitness varied with group size. In contrast to typical social evolution models of quorum sensing which predict higher response to signal at larger group size, the pherotype with highest responsiveness to signals performed best in smaller hosts where infections have a lower pathogen group size. In this system, low signal abundance appears to limit fitness in hosts, while the optimal level of response to signals varies in different host environments. IMPORTANCE Quorum sensing describes the ability of microbes to alter gene regulation according to their local population size. Some successful theory suggests that this is a form of cooperation, namely, investment in shared products is only worthwhile if there are sufficient bacteria making the same product. This theory can explain the genetic diversity in these signaling systems in Gram-positive bacteria, such as Bacillus and Staphylococcus sp. The possible advantages gained by rare genotypes (which can exploit the products of their more common neighbors) could explain why different genotypes can coexist. We show that while these social interactions can occur in simple laboratory experiments, they do not occur in naturalistic infections using an invertebrate pathogen, Bacillus thuringiensis. Instead, our results suggest that different genotypes are adapted to differently sized hosts. Overall, social models are not easily applied to this system, implying that a different explanation for this form of quorum sensing is required.

scholarly journals Bacteria Floc, but Do They Flock? Insights from Population Interaction Models of Quorum Sensing

mBio ◽  
2019 ◽  
Vol 10 (3) ◽  
Author(s):  
Hana Ueda ◽  
Kristina Stephens ◽  
Konstantina Trivisa ◽  
William E. Bentley
Keyword(s):  
Quorum Sensing ◽  
Bacterial Chemotaxis ◽  
Higher Order ◽  
Number Density ◽  
Bacterial Populations ◽  
Content Type ◽  
Cell Position ◽  
Active Bacteria ◽  
Population Interaction ◽  
Flocking Behavior

ABSTRACT Quorum sensing (QS) enables coordinated, population-wide behavior. QS-active bacteria “communicate” their number density using autoinducers which they synthesize, collect, and interpret. Tangentially, chemotactic bacteria migrate, seeking out nutrients and other molecules. It has long been hypothesized that bacterial behaviors, such as chemotaxis, were the primordial progenitors of complex behaviors of higher-order organisms. Recently, QS was linked to chemotaxis, yet the notion that these behaviors can together contribute to higher-order behaviors has not been shown. Here, we mathematically link flocking behavior, commonly observed in fish and birds, to bacterial chemotaxis and QS by constructing a phenomenological model of population-scale QS-mediated phenomena. Specifically, we recast a previously developed mathematical model of flocking and found that simulated bacterial behaviors aligned well with well-known QS behaviors. This relatively simple system of ordinary differential equations affords analytical analysis of asymptotic behavior and describes cell position and velocity, QS-mediated protein expression, and the surrounding concentrations of an autoinducer. Further, heuristic explorations of the model revealed that the emergence of “migratory” subpopulations occurs only when chemotaxis is directly linked to QS. That is, behaviors were simulated when chemotaxis was coupled to QS and when not. When coupled, the bacterial flocking model predicts the formation of two distinct groups of cells migrating at different speeds in their journey toward an attractant. This is qualitatively similar to phenomena spotted in our Escherichia coli chemotaxis experiments as well as in analogous work observed over 50 years ago. IMPORTANCE Our modeling efforts show how cell density can affect chemotaxis; they help to explain the roots of subgroup formation in bacterial populations. Our work also reinforces the notion that bacterial mechanisms are at times exhibited in higher-order organisms.

scholarly journals Export of Rgg Quorum Sensing Peptides is Mediated by the PptAB ABC Transporter in Streptococcus Thermophilus Strain LMD-9

Genes ◽  
2020 ◽  
Vol 11 (9) ◽  
pp. 1096
Author(s):  
Abarna Lingeswaran ◽  
Coralie Metton ◽  
Céline Henry ◽  
Véronique Monnet ◽  
Vincent Juillard ◽  
...  
Keyword(s):  
Quorum Sensing ◽  
Streptococcus Thermophilus ◽  
Gram Positive Bacteria ◽  
Hydrophobic Peptides ◽  
Sensing Systems ◽  
Signaling Peptides ◽  
Genes Encoding ◽  
Liquid Chromatography Tandem Mass ◽  
Peptide Secretion ◽  
And Staphylococcus Aureus

In streptococci, intracellular quorum sensing pathways are based on quorum-sensing systems that are responsible for peptide secretion, maturation, and reimport. These peptides then interact with Rgg or ComR transcriptional regulators in the Rap, Rgg, NprR, PlcR, and PrgX (RRNPP) family, whose members are found in Gram-positive bacteria. Short hydrophobic peptides (SHP) interact with Rgg whereas ComS peptides interact with ComR regulators. To date, in Streptococcus thermophilus, peptide secretion, maturation, and extracellular fate have received little attention, even though this species has several (at least five) genes encoding Rgg regulators and one encoding a ComR regulator. We studied pheromone export in this species, focusing our attention on PptAB, which is an exporter of signaling peptides previously identified in Enterococcus faecalis, pathogenic streptococci and Staphylococcus aureus. In the S. thermophilus strain LMD-9, we showed that PptAB controlled three regulation systems, two SHP/Rgg systems (SHP/Rgg1358 and SHP/Rgg1299), and the ComS/ComR system, while using transcriptional fusions and that PptAB helped to produce and export at least three different mature SHPs (SHP1358, SHP1299, and SHP279) peptides while using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Using a deep sequencing approach (RNAseq), we showed that the exporter PptAB, the membrane protease Eep, and the oligopeptide importer Ami controlled the transcription of the genes that were located downstream from the five non-truncated rgg genes as well as few distal genes. This led us to propose that the five non-truncated shp/rgg loci were functional. Only three shp genes were expressed in our experimental condition. Thus, this transcriptome analysis also highlighted the complex interconnected network that exists between SHP/Rgg systems, where a few homologous signaling peptides likely interact with different regulators.

scholarly journals Nitrogen Source Stabilization of Quorum Sensing in the Pseudomonas aeruginosa Bioaugmentation Strain SD-1

2017 ◽  
Vol 83 (16) ◽  
Author(s):  
Mei-Zhen Wang ◽  
Bai-Min Lai ◽  
Ajai A. Dandekar ◽  
Yu-Sheng Yang ◽  
Na Li ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Quorum Sensing ◽  
Nitrogen Source ◽  
Laboratory Strain ◽  
Nitrogen Sources ◽  
Industrial Applications ◽  
Bacterial Populations ◽  
Content Type ◽  
Wastewater Stream ◽  
The Stability

ABSTRACT Pseudomonas aeruginosa SD-1 is efficient at degrading aromatic compounds and can therefore contribute to the bioremediation of wastewater. P. aeruginosa uses quorum sensing (QS) to regulate the production of numerous secreted “public goods.” In wastewater bioaugmentation applications, there are myriad nitrogen sources, and we queried whether various nitrogen sources impact the stabilities of both QS and the bacterial populations. In a laboratory strain of P. aeruginosa, PAO1, the absence of a nitrogen source has been shown to destabilize these populations through the emergence of QS mutant “cheaters.” We tested the ability of SD-1 to grow in casein broth, a condition that requires QS for growth, when the nitrogen source with either NH4Cl, NaNO3, or NaNO2 or with no added nitrogen source. There was great variability in susceptibility to invasion by QS mutant cheaters and, by extension, the stability of the SD-1 population. When grown with NH4Cl as an extra nitrogen source, no population collapse was observed; by contrast, two-thirds of cultures grown in the presence of NaNO2 collapsed. In the populations that collapsed, the frequency of social cheaters exceeded 40%. NaNO3 and NaNO2 directly favor QS mutants of P. aeruginosa SD-1. Although the mechanism by which these nitrogen sources act is not clear, these data indicate that the metabolism of nitrogen can affect the stability of bacterial populations, an important observation for continuing industrial applications with this species. IMPORTANCE Bioaugmentation as a method to help remediate wastewater pollutant streams holds significant potential to enhance traditional methods of treatment. Addition of microbes that can catabolize organic pollutants can be an effective method to remove several toxic compounds. Such bioaugmented strains of bacteria have been shown to be susceptible to competition from the microbiota that are present in wastewater streams, limiting their potential effectiveness. Here, we show that bioaugmentation strains of bacteria might also be susceptible to invasion by social cheaters and that the nitrogen sources available in the wastewater might influence the ability of cheaters to overtake the bioaugmentation strains. Our results imply that control over the nitrogen sources in a wastewater stream or selective addition of certain nitrogen sources could help stabilize bioaugmentation strains of bacteria.

scholarly journals Antagonistic Rgg Regulators Mediate Quorum Sensing via Competitive DNA Binding in Streptococcus pyogenes

mBio ◽  
2012 ◽  
Vol 3 (6) ◽  
Author(s):  
Breah LaSarre ◽  
Chaitanya Aggarwal ◽  
Michael J. Federle
Keyword(s):  
Dna Binding ◽  
Quorum Sensing ◽  
Streptococcus Pyogenes ◽  
Target Genes ◽  
Transcriptional Regulators ◽  
Content Type ◽  
Bacterial Physiology ◽  
Signaling Peptides ◽  
Direct Competition ◽  
Target Promoters

ABSTRACTRecent studies have established the fact that multiple members of the Rgg family of transcriptional regulators serve as key components of quorum sensing (QS) pathways that utilize peptides as intercellular signaling molecules. We previously described a novel QS system inStreptococcus pyogeneswhich utilizes two Rgg-family regulators (Rgg2 and Rgg3) that respond to neighboring signaling peptides (SHP2 and SHP3) to control gene expression and biofilm formation. We have shown that Rgg2 is a transcriptional activator of target genes, whereas Rgg3 represses expression of these genes, and that SHPs function to activate the QS system. The mechanisms by which Rgg proteins regulate both QS-dependent and QS-independent processes remain poorly defined; thus, we sought to further elucidate how Rgg2 and Rgg3 mediate gene regulation. Here we provide evidence thatS. pyogenesemploys a unique mechanism of direct competition between the antagonistic, peptide-responsive proteins Rgg2 and Rgg3 for binding at target promoters. The highly conserved, shared binding sites for Rgg2 and Rgg3 are located proximal to the −35 nucleotide in the target promoters, and the direct competition between the two regulators results in concentration-dependent, exclusive occupation of the target promoters that can be skewed in favor of Rgg2in vitroby the presence of SHP. These results suggest that exclusionary binding of target promoters by Rgg3 may prevent Rgg2 binding under SHP-limiting conditions, thereby preventing premature induction of the quorum sensing circuit.IMPORTANCERgg-family transcriptional regulators are widespread among low-G+C Gram-positive bacteria and in many cases contribute to bacterial physiology and virulence. Only recently was it discovered that several Rgg proteins function in cell-to-cell communication (quorum sensing [QS]) via direct interaction with signaling peptides. The mechanism(s) by which Rgg proteins mediate regulation is poorly understood, and further insight into Rgg function is anticipated to be of great importance for the understanding of both regulatory-network architecture and intercellular communication in Rgg-containing species. The results of this study on the Rgg2/3 QS circuit ofS. pyogenesdemonstrate that DNA binding of target promoters by the activator Rgg2 is directly inhibited by competitive binding by the repressor Rgg3, thereby preventing transcriptional activation of the target genes and premature induction of the QS circuit. This is a unique regulatory mechanism among Rgg proteins and other peptide-responsive QS regulators.

scholarly journals Phenotypic Heterogeneity, a Phenomenon That May Explain Why Quorum Sensing Does Not Always Result in Truly Homogenous Cell Behavior

2015 ◽  
Vol 81 (16) ◽  
pp. 5280-5289 ◽  
Author(s):  
Jessica Grote ◽  
Dagmar Krysciak ◽  
Wolfgang R. Streit
Keyword(s):  
Quorum Sensing ◽  
Regulatory Networks ◽  
Phenotypic Heterogeneity ◽  
Dna Uptake ◽  
Bacterial Populations ◽  
Content Type ◽  
Heterogeneous Behavior ◽  
Heterogeneous Expression ◽  
Bacterial Fitness ◽  
The Many

ABSTRACTPhenotypic heterogeneity describes the occurrence of “nonconformist” cells within an isogenic population. The nonconformists show an expression profile partially different from that of the remainder of the population. Phenotypic heterogeneity affects many aspects of the different bacterial lifestyles, and it is assumed that it increases bacterial fitness and the chances for survival of the whole population or smaller subpopulations in unfavorable environments. Well-known examples for phenotypic heterogeneity have been associated with antibiotic resistance and frequently occurring persister cells. Other examples include heterogeneous behavior within biofilms, DNA uptake and bacterial competence, motility (i.e., the synthesis of additional flagella), onset of spore formation, lysis of phages within a small subpopulation, and others. Interestingly, phenotypic heterogeneity was recently also observed with respect to quorum-sensing (QS)-dependent processes, and the expression of autoinducer (AI) synthase genes and other QS-dependent genes was found to be highly heterogeneous at a single-cell level. This phenomenon was observed in several Gram-negative bacteria affiliated with the generaVibrio,Dinoroseobacter,Pseudomonas,Sinorhizobium, andMesorhizobium. A similar observation was made for the Gram-positive bacteriumListeria monocytogenes. Since AI molecules have historically been thought to be the keys to homogeneous behavior within isogenic populations, the observation of heterogeneous expression is quite intriguing and adds a new level of complexity to the QS-dependent regulatory networks. All together, the many examples of phenotypic heterogeneity imply that we may have to partially revise the concept of homogeneous and coordinated gene expression in isogenic bacterial populations.

scholarly journals Processing, Export, and Identification of Novel Linear Peptides from Staphylococcus aureus

mBio ◽  
2020 ◽  
Vol 11 (2) ◽  
Author(s):  
Katrin Schilcher ◽  
Lindsay K. Caesar ◽  
Nadja B. Cech ◽  
Alexander R. Horswill
Keyword(s):  
Staphylococcus Aureus ◽  
Bacterial Gene ◽  
Content Type ◽  
Gram Positive Bacteria ◽  
Secretion Pathway ◽  
Bacterial Gene Expression ◽  
Signaling Peptides ◽  
Invasive Infections ◽  
Novel Processing ◽  
First Time

ABSTRACT Staphylococcus aureus can colonize the human host and cause a variety of superficial and invasive infections. The success of S. aureus as a pathogen derives from its ability to modulate its virulence through the release, sensing of and response to cyclic signaling peptides. Here we provide, for the first time, evidence that S. aureus processes and secretes small linear peptides through a specialized pathway that converts a lipoprotein leader into an extracellular peptide signal. We have identified and confirmed the machinery for each step and demonstrate that the putative membrane metalloprotease Eep and the EcsAB transporter are required to complete the processing and secretion of the peptides. In addition, we have identified several linear peptides, including the interspecies signaling molecule staph-cAM373, that are dependent on this processing and secretion pathway. These findings are particularly important because multiple Gram-positive bacteria rely on small linear peptides to control bacterial gene expression and virulence. IMPORTANCE Here, we provide evidence indicating that S. aureus secretes small linear peptides into the environment via a novel processing and secretion pathway. The discovery of a specialized pathway for the production of small linear peptides and the identification of these peptides leads to several important questions regarding their role in S. aureus biology, most interestingly, their potential to act as signaling molecules. The observations in this study provide a foundation for further in-depth studies into the biological activity of small linear peptides in S. aureus.

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