Competence stimulating peptide

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Competence stimulating peptide (CSP), a chemical messenger assisting quorum sensing initiation, exists in many bacterial genera. Bacterial transformation of deoxyribonucleic acids (DNA) is driven by CSP coupled quorum sensing. [1]

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Here is a gram stain of Streptococcus pneumoniae - our quorum sensing culprit. The dark purple signifies gram positive bacteria. Gram stain of Streptococcus pneumoniae.jpg
Here is a gram stain of Streptococcus pneumoniae - our quorum sensing culprit. The dark purple signifies gram positive bacteria.

Competence stimulating peptides are a subset of proteins that promote quorum sensing in numerous bacterial genera including Streptococcus and Bacillus. Quorum sensing contributes to regulation of specific gene expressions in response to cell population density fluctuations. Streptococcus pneumoniae, a highly studied Gram-positive bacteria, is capable of quorum sensing and can release auto inducers, chemical signals that increase as concentration based on density. Competence stimulating peptide are part of a unique form of regulation involved in DNA processing. The form of DNA processing starts abruptly and at the same time in all cells when in a constantly or exponentially growing culture, and then growth rapidly decreases after about 12 minutes of exponential growth.

Background

Competence is the ability of bacteria to pull DNA fragments from the environment and integrate it into their chromosome. Competence stimulating peptides (CSP) are a 17-amino acid signal peptide triggers quorum sensing, which aids competence, biofilm formation, and virulence. The propensity of S. pneumoniae to become competent is critical to the bacterium’s development of antibiotic resistance. [2]

A substantial fraction of cells in the culture of species whose appearance of competence has been studied shows that specific growth conditions (ex. growth-limiting conditions) have led to the development of competence. S. pneumonia is unique in the sense that virtually all cells of a culture develop the ability to become competent at the same time. The density that the cells have reached during exponential growth plays a role at determining when the competency is triggered. This competency period only lasts for a short period of time, and studies indicate that this does not affect the growth rate of the culture. [3] There are two main specificity groups that S. pneumoniae can be divided into based on the CSP signal they produce and their compatible receptors. The CSP1 signal is received by receptor ComD1 and the CSP2 signal is received by ComD2. [2]

Physiology and biochemistry

Streptococcus pneumoniae is one of the mostly highly studied bacterial species containing CSP, though other genus and species also utilize the hormone-like protein. [1] [4] [5] Variations in structure, [6] receptor specificity, and codon sequence occur even between different strains of the same species. However, homology between CSP's retain a single negatively charged N-terminus, an arginine residue in position three (C3), and a positively charged C-terminus. Signal-receptor specificity is demonstrated in Streptococcal species through the relationship between CSP1 and CSP2 signals, and the receptors ComD1 and ComD2. Variations of receptor specificity and composition can be estimated based on nuclear magnetic resonance (NMR) spectroscopy analysis. [2]

Alterations in the structure of CSP signals, such as CSP1 and CSP2, are shown to inhibit the cellular response to these peptides, often resulting in reduced biofilm production. [7] Replacement of the first glutamate residue in CSP1 inhibits receptor activation of competency genes, and hydrophobic regions on the CSP1 molecule play key roles in effective ComD1 and Com2 binding. [8] Interspecies interactions between biofilm producing organisms induce the release of chemical signals that inhibit binding or receptor activation in competence stimulating processes. [9]

Initiation of DNA transformation begins as a threshold concentration of CSP is met within a bacterial cell. Cellular density is proportional to CSP concentration. After meeting threshold concentration, transmembrane histidine kinases are activated via binding of corresponding peptides. Regulator proteins in turn are phosphorylated by the activated kinases, thereby inducing competency gene expression. Such genes produce proteins responsible for inducing DNA transformation. [10]

Implications in health and industry

Quorum sensing bacteria within the human microbiome are responsible for many diseases including Sinusitis, [11] Otitis media, [11] [12] Pneumonia, [11] Bacteraemia, [13] Osteomyelitis, Septic arthritis, Meningitis. [14] In the United States alone there is a death toll of >22 000 a year tracing back to this pathogen. [15] S. pneumoniae uses the competence stimulating peptide and quorum sensing to initiate its attack, establish an infection, and develop antibiotic resistance genes. Overall competence stimulating peptide allows S. pneumoniae to initiate a more pervading attack on the human host.

Currently in health and industry, studies center on explaining and intercepting the competence region within the S. pneumoniae. The goal is to limit cell-cell communication with the hopes of attenuating S. pneumoniae infectivity. [16] Inhibiting the competence stimulating peptide shows potential as a way to combat pneumococcal infections. [15]

Related Research Articles

<i>Streptococcus</i> Genus of bacteria

Streptococcus is a genus of gram-positive coccus or spherical bacteria that belongs to the family Streptococcaceae, within the order Lactobacillales, in the phylum Bacillota. Cell division in streptococci occurs along a single axis, thus when growing they tend to form pairs or chains, which may appear bent or twisted. This differs from staphylococci, which divide along multiple axes, thereby generating irregular, grape-like clusters of cells. Most streptococci are oxidase-negative and catalase-negative, and many are facultative anaerobes.

<span class="mw-page-title-main">Biofilm</span> Aggregation of bacteria or cells on a surface

A biofilm is a syntrophic community of microorganisms in which cells stick to each other and often also to a surface. These adherent cells become embedded within a slimy extracellular matrix that is composed of extracellular polymeric substances (EPSs). The cells within the biofilm produce the EPS components, which are typically a polymeric combination of extracellular polysaccharides, proteins, lipids and DNA. Because they have a three-dimensional structure and represent a community lifestyle for microorganisms, they have been metaphorically described as "cities for microbes".

<i>Streptococcus pyogenes</i> Species of bacterium

Streptococcus pyogenes is a species of Gram-positive, aerotolerant bacteria in the genus Streptococcus. These bacteria are extracellular, and made up of non-motile and non-sporing cocci that tend to link in chains. They are clinically important for humans, as they are an infrequent, but usually pathogenic, part of the skin microbiota that can cause Group A streptococcal infection. S. pyogenes is the predominant species harboring the Lancefield group A antigen, and is often called group A Streptococcus (GAS). However, both Streptococcus dysgalactiae and the Streptococcus anginosus group can possess group A antigen as well. Group A streptococci, when grown on blood agar, typically produce small (2–3 mm) zones of beta-hemolysis, a complete destruction of red blood cells. The name group A (beta-hemolytic) Streptococcus is thus also used.

In biology, quorum sensing or quorum signaling (QS) is the process of cell to cell communication which allows bacteria the ability to detect and respond to cell population density by gene regulation, typically as a means of acclimating to environmental disadvantages.

<i>Streptococcus pneumoniae</i> Species of bacterium

Streptococcus pneumoniae, or pneumococcus, is a Gram-positive, spherical bacteria, alpha-hemolytic member of the genus Streptococcus. They are usually found in pairs (diplococci) and do not form spores and are non motile. As a significant human pathogenic bacterium S. pneumoniae was recognized as a major cause of pneumonia in the late 19th century, and is the subject of many humoral immunity studies.

<span class="mw-page-title-main">Transformation (genetics)</span> Genetic alteration of a cell by uptake of genetic material from the environment

In molecular biology and genetics, transformation is the genetic alteration of a cell resulting from the direct uptake and incorporation of exogenous genetic material from its surroundings through the cell membrane(s). For transformation to take place, the recipient bacterium must be in a state of competence, which might occur in nature as a time-limited response to environmental conditions such as starvation and cell density, and may also be induced in a laboratory.

<i>Streptococcus mutans</i> Species of bacterium

Streptococcus mutans is a facultatively anaerobic, gram-positive coccus commonly found in the human oral cavity and is a significant contributor to tooth decay. It is part of the "streptococci", an informal general name for all species in the genus Streptococcus. The microbe was first described by James Kilian Clarke in 1924.

Pneumococcal pneumonia is a type of bacterial pneumonia that is caused by Streptococcus pneumoniae (pneumococcus). It is the most common bacterial pneumonia found in adults, the most common type of community-acquired pneumonia, and one of the common types of pneumococcal infection. The estimated number of Americans with pneumococcal pneumonia is 900,000 annually, with almost 400,000 cases hospitalized and fatalities accounting for 5-7% of these cases.

<span class="mw-page-title-main">Natural competence</span> Ability of cells to alter their own genetics by taking up extracellular DNA

In microbiology, genetics, cell biology, and molecular biology, competence is the ability of a cell to alter its genetics by taking up extracellular ("naked") DNA from its environment in the process called transformation. Competence may be differentiated between natural competence, a genetically specified ability of bacteria which is thought to occur under natural conditions as well as in the laboratory, and induced or artificial competence, which arises when cells in laboratory cultures are treated to make them transiently permeable to DNA. Competence allows for rapid adaptation and DNA repair of the cell. This article primarily deals with natural competence in bacteria, although information about artificial competence is also provided.

<i>Streptococcus oralis</i> Species of bacterium

Streptococcus oralis is a Gram positive viridans streptococcus of the Streptococcus mitis group. S. oralis is one of the pioneer species associated with eubiotic dental pellicle biofilms, and can be found in high numbers on most oral surfaces. It has been, however, found to be an opportunistic pathogen as well.

<span class="mw-page-title-main">S-ribosylhomocysteine lyase</span>

The enzyme S-ribosylhomocysteine lyase catalyzes the reaction

<span class="mw-page-title-main">GPR32</span> Human biochemical receptor

G protein-coupled receptor 32, also known as GPR32 or the RvD1 receptor, is a human receptor (biochemistry) belonging to the rhodopsin-like subfamily of G protein-coupled receptors.

Autoinducers are signaling molecules that are produced in response to changes in cell-population density. As the density of quorum sensing bacterial cells increases so does the concentration of the autoinducer. Detection of signal molecules by bacteria acts as stimulation which leads to altered gene expression once the minimal threshold is reached. Quorum sensing is a phenomenon that allows both Gram-negative and Gram-positive bacteria to sense one another and to regulate a wide variety of physiological activities. Such activities include symbiosis, virulence, motility, antibiotic production, and biofilm formation. Autoinducers come in a number of different forms depending on the species, but the effect that they have is similar in many cases. Autoinducers allow bacteria to communicate both within and between different species. This communication alters gene expression and allows bacteria to mount coordinated responses to their environments, in a manner that is comparable to behavior and signaling in higher organisms. Not surprisingly, it has been suggested that quorum sensing may have been an important evolutionary milestone that ultimately gave rise to multicellular life forms.

<span class="mw-page-title-main">Prokaryote</span> Unicellular organism lacking a membrane-bound nucleus

A prokaryote is a single-cell organism whose cell lacks a nucleus and other membrane-bound organelles. The word prokaryote comes from the Ancient Greek πρό 'before' and κάρυον 'nut, kernel'. In the two-empire system arising from the work of Édouard Chatton, prokaryotes were classified within the empire Prokaryota. But in the three-domain system, based upon molecular analysis, prokaryotes are divided into two domains: Bacteria and Archaea. Organisms with nuclei are placed in a third domain, Eukaryota.

Everett Peter Greenberg is an American microbiologist. He is the inaugural Eugene and Martha Nester Professor of Microbiology at the Department of Microbiology of the University of Washington School of Medicine. He is best known for his research on quorum sensing, and has received multiple awards for his work.

An innate immune defect is a defect in the innate immune response that blunts the response to infection. These defects may occur in monocytes, neutrophils, natural killer cells, basophils, mast cells or complement proteins.

RopB transcriptional regulator, also known as RopB/Rgg transcriptional regulator is a transcriptional regulator protein that regulates expression of the extracellularly secreted cysteine protease streptococcal pyrogenic exotoxin B (speB) [See Also: erythrogenic toxins] which is an important virulence factor of Streptococcus pyogenes and is responsible for the dissemination of a host of infectious diseases including strep throat, impetigo, streptococcal toxic shock syndrome, necrotizing fasciitis, and scarlet fever. Functional studies suggest that the ropB multigene regulon is responsible for not only global regulation of virulence but also a wide range of functions from stress response, metabolic function, and two-component signaling. Structural studies implicate ropB's regulatory action being reliant on a complex interaction involving quorum sensing with the leaderless peptide signal speB-inducing peptide (SIP) acting in conjunction with a pH sensitive histidine switch.

<span class="mw-page-title-main">Competence factor</span>

The ability of a cell to successfully incorporate exogenous DNA, or competency, is determined by competence factors. These factors consist of certain cell surface proteins and transcription factors that induce the uptake of DNA.

Diffusible signal factor (DSF) is found in several gram-negative bacteria and play a role in the formation of biofilms, motility, virulence, and antibiotic resistance. Xanthomonas campestris was the first bacteria known to have DSF. The synthesis of the DSF can be seen in rpfF and rpfB enzymes. An understanding of the DSF signaling mechanism could lead to further disease control.

Lipoprotein rotamase A (SlrA), also known as peptidyl prolyl isomerase A (PpiA), functions as a molecular chaperone that operates within the Streptococcus pneumoniae cell membrane-cell wall interface as well as outside the bacteria. SlrA shares homology with the cyclophilin-type peptidyl-prolyl isomerases (PPIases). PPIases accelerate the folding of proteins by catalyzing the cis-trans isomer conversions of peptide bonds in the amino acid proline.

References

  1. 1 2 Suntharalingam, Prashanth; Cvitkovitch, Dennis G. (January 2005). "Quorum sensing in streptococcal biofilm formation". Trends in Microbiology. 13 (1): 3–6. doi:10.1016/j.tim.2004.11.009. ISSN   0966-842X. PMID   15639624.
  2. 1 2 3 Yang, Yifang; Cornilescu, Gabriel; Tal-Gan, Yftah (2018-09-11). "Structural Characterization of Competence-Stimulating Peptide Analogues Reveals Key Features for ComD1 and ComD2 Receptor Binding in Streptococcus pneumoniae". Biochemistry. 57 (36): 5359–5369. doi:10.1021/acs.biochem.8b00653. ISSN   0006-2960. PMC   6145841 . PMID   30125091.
  3. ↑ Morrison, D. A.; Baker, M. F. (November 1979). "Competence for genetic transformation in pneumococcus depends on synthesis of a small set of proteins". Nature. 282 (5735): 215–217. Bibcode:1979Natur.282..215M. doi:10.1038/282215a0. ISSN   1476-4687. PMID   40135. S2CID   4322312.
  4. ↑ Johnsborg, Ola; Kristiansen, Per Eugen; Blomqvist, Trinelise; Håvarstein, Leiv Sigve (March 2006). "A hydrophobic patch in the competence-stimulating Peptide, a pneumococcal competence pheromone, is essential for specificity and biological activity". Journal of Bacteriology. 188 (5): 1744–1749. doi:10.1128/JB.188.5.1744-1749.2006. ISSN   0021-9193. PMC   1426553 . PMID   16484185.
  5. ↑ Bikash, Chowdhury Raihan; Hamry, Sally R.; Tal-Gan, Yftah (2018-09-14). "Structure-Activity Relationships of the Competence Stimulating Peptide in Streptococcus mutans Reveal Motifs Critical for Membrane Protease SepM Recognition and ComD Receptor Activation". ACS Infectious Diseases. 4 (9): 1385–1394. doi:10.1021/acsinfecdis.8b00115. ISSN   2373-8227. PMC   6138527 . PMID   29990430.
  6. ↑ "competence stimulating protein - Structure - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2023-10-21.
  7. ↑ Lemme, André; Gröbe, Lothar; Reck, Michael; Tomasch, Jürgen; Wagner-Döbler, Irene (2011-04-15). "Subpopulation-Specific Transcriptome Analysis of Competence-Stimulating-Peptide-Induced Streptococcus mutans". Journal of Bacteriology. 193 (8): 1863–1877. doi:10.1128/JB.01363-10. ISSN   0021-9193. PMC   3133041 . PMID   21317319.
  8. ↑ Yang, Yifang; Tal-Gan, Yftah (August 2019). "Exploring the competence stimulating peptide (CSP) N-terminal requirements for effective ComD receptor activation in group1 Streptococcus pneumoniae". Bioorganic Chemistry. 89: 102987. doi:10.1016/j.bioorg.2019.102987. PMC   6656601 . PMID   31132605.
  9. ↑ Tamura, S.; Yonezawa, H.; Motegi, M.; Nakao, R.; Yoneda, S.; Watanabe, H.; Yamazaki, T.; Senpuku, H. (April 2009). "Inhibiting effects of Streptococcus salivarius on competence-stimulating peptide-dependent biofilm formation by Streptococcus mutans". Oral Microbiology and Immunology. 24 (2): 152–161. doi:10.1111/j.1399-302X.2008.00489.x. ISSN   0902-0055. PMID   19239643.
  10. ↑ Yang, Yifang; Cornilescu, Gabriel; Tal-Gan, Yftah (2018-09-11). "Structural Characterization of Competence-Stimulating Peptide Analogues Reveals Key Features for ComD1 and ComD2 Receptor Binding in Streptococcus pneumoniae". Biochemistry. 57 (36): 5359–5369. doi:10.1021/acs.biochem.8b00653. ISSN   0006-2960. PMC   6145841 . PMID   30125091.
  11. 1 2 3 Gaudin, Julie; Thayalakulasingam, Theepha (2023-09-07). "Invasive Pneumococcal Disease and COVID-19 With Acute Otitis Media and a Tegmen Tympani Defect". Cureus. 15 (9): e44869. doi: 10.7759/cureus.44869 . ISSN   2168-8184. PMC   10560565 . PMID   37814724.
  12. ↑ Horhat, Raluca; Horhat, Florin-Raul; Mocanu, Valeria (2021). "Is Multidrug Resistance in Acute Otitis Media with Streptococcus pneumoniae Associated with a More Severe Disease?". Medical Principles and Practice. 30 (6): 571–578. doi:10.1159/000518720. ISSN   1011-7571. PMC   8739848 . PMID   34348311.
  13. ↑ de Leau, Michelle M; Kuipers, Remko S (April 2021). "Cardiovascular complications of Streptococcus pneumoniae bacteraemia". BMJ Case Reports. 14 (4): e240341. doi:10.1136/bcr-2020-240341. ISSN   1757-790X. PMC   8030674 . PMID   33827874.
  14. ↑ Winegarner, James H; Wittkopp, Jeffrey (2020-05-24). "Streptococcus pneumoniae Meningitis Associated With Over-the-Counter Sinus Irrigation". Cureus. 12 (5): e8258. doi: 10.7759/cureus.8258 . ISSN   2168-8184. PMC   7313434 . PMID   32596076.
  15. 1 2 Koirala, Bimal; Lin, Jingjun; Lau, Gee W.; Tal-Gan, Yftah (2018-11-16). "Development of a Dominant Negative Competence-Stimulating Peptide (dnCSP) that Attenuates Streptococcus pneumoniae Infectivity in a Mouse Model of Acute Pneumonia". ChemBioChem. 19 (22): 2380–2386. doi:10.1002/cbic.201800505. ISSN   1439-4227. PMC   6251734 . PMID   30211457.
  16. ↑ Yang, Yifang; Lin, Jingjun; Harrington, Anthony; Cornilescu, Gabriel; Lau, Gee W.; Tal-Gan, Yftah (2020-01-21). "Designing cyclic competence-stimulating peptide (CSP) analogs with pan-group quorum-sensing inhibition activity in Streptococcus pneumoniae". Proceedings of the National Academy of Sciences. 117 (3): 1689–1699. Bibcode:2020PNAS..117.1689Y. doi: 10.1073/pnas.1915812117 . ISSN   0027-8424. PMC   6983377 . PMID   31915298.
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