TargetingQuorum Sensing and Competence Stimulation for Antimicrobial Chemotherapy
Nicholas E. Shepherd,
Rosemary S. Harrison,
David P. Fairlie.
Bacterial resistance to antibiotics is now a serious problem, with traditional classes of antibiotics having gradually
become ineffective. New drugs are therefore needed to target and inhibit novel pathways that affect the growth of
bacteria. An important feature in the survival of bacteria is that they coordinate their efforts together as a colony via secreted
auto-inducing molecules. Competence stimulating peptides (CSPs) are among the quorum sensing pheromones involved
in this coordination. These peptides activate a two-component system in gram-negative bacteria, binding to and activating
a histidine kinase receptor called ComD, which phosphorylates a response regulator called ComE, leading to gene
expression and induction of competence. Competent bacteria are able to take up exogenous DNA and incorporate it into
their own genome. By this mechanism bacteria are able to acquire and share genes encoding antibiotic resistance. Despite
having been studied for over 30 years, this pathway has only recently begun to be explored as a novel approach to modulating
bacterial growth. Antagonists of ComD might block the signaling cascade that leads to competence, while overstimulation
of ComD might also reduce bacterial growth. One possible approach to inhibiting ComD is to examine peptide
sequences of CSPs that activate ComD and attempt to constrain them to bioactive conformations, likely to have higher affinity
due to pre-organization for recognition by the receptor. Thus, small molecules that mimic an alpha helical epitope of
CSPs, the putative ComD binding domain, have been shown here to inhibit growth of bacteria such as S. pneumoniae.
Such alpha helix mimetics may be valuable clues to antibacterial chemotherapeutic agents that utilize a new mechanism to
control bacterial growth.
Keywords: Alpha helix mimetics, antibacterial, antibiotic, competence, pheromone, quorum, Stimulation, Chemotherapy, Competence stimulating peptides (CSPs), ComD.
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