Attenuating the Streptococcus pneumoniae Competence Regulon Using Urea-Bridged Cyclic Dominant-Negative Competence-Stimulating Peptide Analogs

Abstract

Streptococcus pneumoniae (pneumococcus) is a prevalent human pathogen that utilizes the competence regulon quorum sensing circuitry to acquire antibiotic resistance and initiate its attack on the human host. Therefore, targeting the competence regulon can be applied as an anti-infective approach with minimal pressure for resistance development. Herein, we report the construction of a library of urea-bridged cyclic dominant-negative competence-stimulating peptide (dnCSP) derivatives and their evaluation as competitive inhibitors of the competence regulon. Our results reveal the first pneumococcus dual-action CSPs that inhibit the group 1 pneumococcus competence regulon while activating the group 2 pneumococcus competence regulon. Structural analysis indicates that the urea-bridge cyclization stabilizes the bioactive α-helix conformation, while in vivo studies using a mouse model of infection exhibit that the lead dual-action dnCSP, CSP1-E1A-cyc­(Dab6Dab10), attenuates group 1-mediated mortality without significantly reducing the bacterial burden. Overall, our results pave the way for developing novel therapeutics against this notorious pathogen.

Targeting peptide‐based quorum sensing systems for the treatment of gram‐positive bacterial infections

“…[ 51,52 ] Peptide cyclization has also been shown to be an effective approach to increase peptide stability, binding affinity, and specificity to the receptor. [ 54–57 ]…”

“…intended to design and develop pharmacologically enhanced cyclic peptidomimetic scaffolds by utilizing the side chain‐to‐side chain urea‐bridge cyclization chemistry. [ 55 ] This strategy led to the development of the first pneumococcus dual‐action CSP modulator that can block group 1 while activating group 2 pneumococcus competence regulon. This is an interesting finding showing that analogs bearing the E1A modification, a reported key modification in the conversion of CSPs into competitive ComD inhibitors, can activate noncognate pneumococcal ComD receptors.…”

“…[51,52] Peptide cyclization has also been shown to be an effective approach to increase peptide stability, binding affinity, and specificity to the receptor. [54][55][56][57] In vivo studies have been reported determining the efficacy of the peptide modulators in preventing or reducing diseases. For example, our group, together with the Lau lab, reported the development of potent synthetic pneumococcal QS modulators that can attenuate pneumococcal infections in vivo.…”

“…For example, our group, together with the Lau lab, reported the development of potent synthetic pneumococcal QS modulators that can attenuate pneumococcal infections in vivo. [55,56,58] Blocking the Agr QS system to control virulence in S. aureus could be a fruitful target as the pathology of an Agr group IV strain can be attenuated through vaccination with hapten-linked AIP-4. [59] Recently, Blackwell and co-workers reported a stable and potent synthetic peptide-based inhibitor of the S. aureus agr system attenuating S. aureus (MRSA) infection in an in vivo mouse model of skin infection.…”

Electrostatic Adsorption of Dense AuNPs onto Silica Core as High-Performance SERS Tag for Sensitive Immunochromatographic Detection of Streptococcus pneumoniae

“…Streptococcus pneumoniae ( S. pneumoniae ) is a dangerous respiratory pathogen that causes serious diseases such as pneumonia, sepsis, otitis media, and meningitis, and kills more than one million people worldwide a year [ 1 , 2 , 3 ]. S. pneumoniae easily affects children, the elderly, and immunocompromised people, and causes clinical symptoms (e.g., cough, fever, fatigued) resembling respiratory virus infection [ 4 ].…”