1 research outputs found
Structure–Activity Relationships of the Competence Stimulating Peptides (CSPs) in <i>Streptococcus pneumoniae</i> Reveal Motifs Critical for Intra-group and Cross-group ComD Receptor Activation
<i>Streptococcus pneumoniae</i> is a highly recombinogenic
human pathogen that utilizes the competence stimulating peptide (CSP)-based
quorum sensing (QS) circuitry to acquire antibiotic resistance genes
from the environment and initiate its attack on the human host. Modulation
of QS in this bacterium, either inhibition or activation, can therefore
be used to attenuate <i>S. pneumoniae</i> infectivity and
slow down pneumococcal resistance development. In this study, we set
to determine the molecular mechanism that drives CSP:receptor binding
and identify CSP-based QS modulators with distinct activity profiles.
To this end, we conducted systematic replacement of the amino acid
residues in the two major CSP signals (CSP1 and CSP2) and assessed
the ability of the mutated analogs to modulate QS against both cognate
and noncognate ComD receptors. We then evaluated the overall 3D structures
of these analogs using circular dichroism (CD) to correlate between
the structure and function of these peptides. Our CD analysis revealed
a strong correlation between α-helicity and bioactivity for
both specificity groups (CSP1 and CSP2). Furthermore, we identified
the first pan-group QS activator and the most potent group-II QS inhibitor
to date. These chemical probes can be used to study the role of QS
in <i>S. pneumoniae</i> and as scaffolds for the design
of QS-based anti-infective therapeutics against <i>S. pneumoniae</i> infections