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Pharmacological Evaluation of Synthetic Dominant-Negative Peptides Derived from the Competence-Stimulating Peptide of Streptococcus pneumoniae.

ABSTRACT: The competence regulon of Streptococcus pneumoniae (pneumococcus) is a quorum-sensing circuitry that regulates the ability of this pathogen to acquire antibiotic resistance or perform serotype switching, leading to vaccine-escape serotypes, via horizontal gene transfer, as well as initiate virulence. Induction of the competence regulon is centered on binding of the competence-stimulating peptide (CSP) to its cognate receptor, ComD. We have recently synthesized multiple dominant-negative peptide analogs capable of inhibiting competence induction and virulence in S. pneumoniae. However, the pharmacodynamics and safety profiles of these peptide drug leads have not been characterized. Therefore, in this study, we compared the biostability of cyanine-7.5-labeled wild-type CSPs versus dominant-negative peptide analogs (dnCSPs) spatiotemporally by using an IVIS Spectrum in vivo imaging system. Moreover, in vitro cytotoxicity and in vivo toxicity were evaluated. We conclude that our best peptide analog, CSP1-E1A-cyc(Dap6E10), is an attractive therapeutic agent against pneumococcal infection with superior safety and pharmacokinetics profiles.

SUBMITTER: Oh MW

PROVIDER: S-EPMC9112410 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Pharmacological Evaluation of Synthetic Dominant-Negative Peptides Derived from the Competence-Stimulating Peptide of <i>Streptococcus pneumoniae</i>.

Oh Myung Whan MW Lella Muralikrishna M Kuo Shanny Hsuan SH Tal-Gan Yftah Y Lau Gee W GW

ACS pharmacology & translational science 20220420 5

The competence regulon of <i>Streptococcus pneumoniae</i> (pneumococcus) is a quorum-sensing circuitry that regulates the ability of this pathogen to acquire antibiotic resistance or perform serotype switching, leading to vaccine-escape serotypes, via horizontal gene transfer, as well as initiate virulence. Induction of the competence regulon is centered on binding of the competence-stimulating peptide (CSP) to its cognate receptor, ComD. We have recently synthesized multiple dominant-negative p ...[more]

PMID: 35592433

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Project description:Streptococcus gallolyticus subsp. 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 that S. gallolyticus subsp. gallolyticus uses a ComRS pathway, one of many Streptococcus quorum-sensing circuitries, for competence. However, thus far, the ubiquitous ComABCDE pathway has not been studied, nor has its regulatory role in S. gallolyticus subsp. gallolyticus We therefore sought to study the S. gallolyticus subsp. gallolyticus ComABCDE 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 both Streptococcus pneumoniae and Streptococcus mutans Our data show that S. gallolyticus subsp. gallolyticus TX20005 produces a 21-mer CSP signal, which differs from CSP signals of other Streptococcus species 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 other Streptococcus species. This study provides the first evidence that S. gallolyticus subsp. gallolyticus utilizes quorum sensing to eliminate competitors, presenting a potential pathway to target this emerging human pathogen.IMPORTANCEStreptococcus gallolyticus subsp. gallolyticus is 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 in S. gallolyticus subsp. 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.

Dataset Information

Pharmacological Evaluation of Synthetic Dominant-Negative Peptides Derived from the Competence-Stimulating Peptide of Streptococcus pneumoniae.

Publications

Pharmacological Evaluation of Synthetic Dominant-Negative Peptides Derived from the Competence-Stimulating Peptide of <i>Streptococcus pneumoniae</i>.

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