Optimizing CSP1 analogs for modulating quorum sensing inStreptococcus pneumoniaewith bulky, hydrophobic nonproteogenic amino acid substitutions

Abstract

The prompt appearance of multiantibiotic-resistant bacteria necessitates finding alternative treatments that can attenuate bacterial infections while minimizing the rate of antibiotic resistance development. Streptococcus pneumoniae, a notorious human pathogen, is...

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

“…Follow‐up studies have focused on optimizing the degree of occupancy of the CSP1 binding pockets within the ComD1 receptor by utilizing conservative substitutions at these key hydrophobic residues of CSP1. [ 92–94 ] Through the incorporation of bulkier, hydrophobic nonproteogenic amino acids, Milly et al were able to develop pneumococcal QS modulators with high potency and superior metabolic stability, while remaining nontoxic against mammalian cells. [ 94 ]…”

“…[ 92–94 ] Through the incorporation of bulkier, hydrophobic nonproteogenic amino acids, Milly et al were able to develop pneumococcal QS modulators with high potency and superior metabolic stability, while remaining nontoxic against mammalian cells. [ 94 ]…”

“…Follow-up studies have focused on optimizing the degree of occupancy of the CSP1 binding pockets within the ComD1 receptor by utilizing conservative substitutions at these key hydrophobic residues of CSP1. [92][93][94] Through the incorporation of bulkier, hydrophobic nonproteogenic amino acids, Milly et al were able to develop pneumococcal QS modulators with high potency and superior metabolic stability, while remaining nontoxic against mammalian cells. [94] The first position on the pherotype 1 AIP (CSP1, Table 1; with its unique primary structure, each CSP represents a separate pheromone type-pherotype) was found to be necessary for competence development, as Glu1 to Ala mutation (to afford CSP1-E1A) was sufficient to convert the signaling peptide into a competitive inhibitor capable of inhibiting competence induction and regulation of down-stream genes in S. pneumoniae.…”

“…[92][93][94] Through the incorporation of bulkier, hydrophobic nonproteogenic amino acids, Milly et al were able to develop pneumococcal QS modulators with high potency and superior metabolic stability, while remaining nontoxic against mammalian cells. [94] The first position on the pherotype 1 AIP (CSP1, Table 1; with its unique primary structure, each CSP represents a separate pheromone type-pherotype) was found to be necessary for competence development, as Glu1 to Ala mutation (to afford CSP1-E1A) was sufficient to convert the signaling peptide into a competitive inhibitor capable of inhibiting competence induction and regulation of down-stream genes in S. pneumoniae. [42] The N-terminal first residue (Glu1) was further investigated through the implication of amino acids (AAs) with different side-chain length, polarity, and chirality.…”

Developing multispecies quorum-sensing modulators based on the Streptococcus mitis competence-stimulating peptide

“…This well-known process is used by competent streptococci to acquire genetic material from the surroundings, including genes that confer antibiotic resistance, as well as genes that regulate a wide range of functions related to pathogenicity, such as virulence factor production and biofilm formation. In both S. mitis and S. pneumoniae , competence is regulated by a density dependent quorum-sensing (QS) system, which is centered on competence pheromones, also known as competence stimulating peptides (CSPs) ( 17 , 18 , 19 , 20 ). QS is a ubiquitous process that allows bacteria to assess their population density and alter their gene expression once they achieve high cell number ( 21 , 22 ).…”