Targeting quorum sensing and competence stimulation for antimicrobial chemotherapy.
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.
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Qld 4072, Australia.
Nicholas E
NE
Shepherd
Rosemary S
RS
Harrison
David P
DP
Fairlie
D000595:Amino Acid Sequence; D000890:Anti-Infective Agents / Q000627:therapeutic use*; D001426:Bacterial Proteins / Q000737:chemistry; D004352:Drug Resistance, Microbial; D006801:Humans; D008969:Molecular Sequence Data; D010766:Phosphorylation; D053038:Quorum Sensing; D017386:Sequence Homology, Amino Acid; D013291:Streptococcus / Q000737:chemistry
D000890:Anti-Infective Agents; D001426:Bacterial Proteins