2 research outputs found
Structure–Activity Relationships of the Competence Stimulating Peptide in <i>Streptococcus mutans</i> Reveal Motifs Critical for Membrane Protease SepM Recognition and ComD Receptor Activation
<i>Streptococcus
mutans</i> (<i>S. mutans</i>) is a Gram-positive
human pathogen that is one of the major contributors to dental caries,
a condition with an economic cost of over $100 billion per year in
the United States. <i>S. mutans</i> secretes a 21-amino-acid
peptide termed the competence stimulating peptide (21-CSP) to assess
its population density in a process termed quorum sensing (QS) and
to initiate a variety of phenotypes such as biofilm formation and
bacteriocin production. 21-CSP is processed by a membrane bound protease
SepM into active 18-CSP, which then binds to the ComD receptor. This
study seeks to determine the molecular mechanism that ties 21-CSP:SepM
recognition and 18-CSP:ComD receptor binding and to identify QS modulators
with distinct activity profiles. To this end, we conducted systematic
replacement of the amino acid residues in both 21-CSP and 18-CSP and
assessed the ability of the mutated analogs to modulate QS. We identified
residues that are important to SepM recognition and ComD receptor
binding. Our results shed light on the <i>S. mutans</i> competence QS pathway at the molecular level. Moreover, our structural
insights of the CSP signal can be used to design QS-based anti-infective
therapeutics against <i>S. mutans</i>
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