TY - JOUR
T1 - Attenuating the Streptococcus pneumoniae Competence Regulon Using Urea-Bridged Cyclic Dominant-Negative Competence-Stimulating Peptide Analogs
AU - Lella, Muralikrishna
AU - Oh, Myung Whan
AU - Kuo, Shanny Hsuan
AU - Lau, Gee W.
AU - Tal-Gan, Yftah
N1 - This work was supported by a grant from the National Institutes of Health (R01HL142626).
PY - 2022/5/12
Y1 - 2022/5/12
N2 - 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.
AB - 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.
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U2 - 10.1021/acs.jmedchem.2c00148
DO - 10.1021/acs.jmedchem.2c00148
M3 - Article
C2 - 35452241
AN - SCOPUS:85129250381
SN - 0022-2623
VL - 65
SP - 6826
EP - 6839
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 9
ER -