TargetingQuorum Sensing and Competence Stimulation for Antimicrobial Chemotherapy

Abstract

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.

Structural Insights into Streptococcal Competence Regulation by the Cell-to-Cell Communication System ComRS

“…Inhibiting competence development thus constitutes an interesting target in drug discovery. Studies have already been undertaken [42], which target the well characterized two-component signaling system ComDE. The latter also regulates competence in Streptococcus pneumoniae via σ X in response to the extracellular Competence-Stimulating-Peptide (called CSP) [43].…”

Constraining Cyclic Peptides To Mimic Protein Structure Motifs

“…[8d, 72, 84-88] Multiple cyclo-(1,5)-[KXXXD] lactam bridged modules have been inserted into biologically active peptide sequences from protein a-helices to downsize proteins to smaller synthetic molecules that maintain potency and stability to biological fluids and proteases. [72] This technique was applied ( Table 1) to inhibiting viral fusion (RSV) (68, 69), [85] (HIV-Rev) (70), [72] anti-bacterials (CSP-1) (71), [86] ORL-1 receptor agonists (72) and antagonists (73), [87] and transcription factor antagonists (cFos) (74). [88] Agonist 72 caused prolonged antinociceptive effects in mice, and these effects could be reversed by co-administering 73.…”

“…The 15residue peptide from MAML1 [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] blocked full length MAML1 binding to the ternary complex, suppressed NOTCH-1 signalling and had anti-leukemic activity in vivo. [99] Inhibitors of the p53-hDM2/hDMX interaction have been developed utilizing i!i + 7 staples (85)(86)(87). The initially reported 82 showed high helicity and affinity for HDM2 and efficacy in mice.…”

Fixierung cyclischer Peptide: Mimetika von Proteinstrukturmotiven

“…Chemie blockiert die Bindung des vollständigen MAML1 an den ternären Komplex, unterdrückt die Signalgebung durch NOTCH-1 und hat eine Antileukämie-Wirkung in vivo. [99] Inhibitoren der p53-hDM2/hDMX-Wechselwirkung wurden unter Einsatz einer i!i + 7-Klammer entwickelt (85)(86)(87). Die eingangs erwähnte Verbindung 82 hat hohe Helixanteile, eine gute Affinität für HDM2 und Wirksamkeit in Mäusen.…”

“…[8d, 72, 84-88] Viele cyclo-(1,5)-[KXXXD]-lactamverbrückte Module sind in biologisch aktive Peptidsequenzen von Protein-a-Helices eingefügt worden, um die Proteine durch kleinere synthetische Moleküle zu ersetzen, die aber die Wirkstärke und Stabilität in biologischen Flüssigkeiten und gegenüber Proteasen behalten. [72] Diese Methode wurde angewendet (Tabelle 1) auf die Hemmung der viralen Fusion (RSV: 68, 69; [85] HIV-Rev: 70), [72] antibakterielle Substanzen (CSP-1) (71), [86] ORL-1-Rezeptoragonisten (72) und -antagonisten (73) [87] sowie Transkriptionsfaktor-Antagonisten (cFos) (74). [88] Agonist 72 lçste langdauernde Schmerzlinderung bei Mäusen aus, die durch die gleichzeitige Verabreichung von 73 umgekehrt werden konnten.…”