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Potent and selective synthetic modulators of a quorum sensing repressor in Pseudomonas aeruginosa identified from second-generation libraries of N-acylated L-homoserine lactones.

ABSTRACT: Bacteria can coordinate group behavior using chemical signals in a process called quorum sensing (QS). The QS system in the opportunistic pathogen Pseudomonas aeruginosa is largely governed by the LasR receptor and its cognate chemical signal, N-(3-oxo)-dodecanoyl L-homoserine lactone (OdDHL). LasR also appears to share this signal with an orphan LuxR-type receptor in P. aeruginosa, termed QscR, which represses LasR activity. Non-native molecules that modulate QscR would represent valuable tools to study the role of this novel QS repressor protein in P. aeruginosa. We performed a critical analysis of previously identified, non-native N-acylated L-homoserine lactone (AHL) activators and inhibitors of QscR to determine a set of structure-activity relationships (SARs). Based on these SAR data, we designed, synthesized, and screened several second-generation libraries of AHLs for new ligands that could target QscR. These studies revealed the most active AHL agonists and antagonists of QscR reported to date, with activities ranging from nanomolar to low micromolar in a QscR bacterial reporter strain. Several of these AHLs were highly selective for QscR over LasR and other LuxR-type receptors. A small subset of the new QscR activators, however, were also found to inhibit LasR; this demonstrates the exciting potential for the synergistic modulation of these integral P. aeruginosa QS receptors by using a single synthetic compound.

SUBMITTER: Mattmann ME

PROVIDER: S-EPMC3431017 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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Potent and selective synthetic modulators of a quorum sensing repressor in Pseudomonas aeruginosa identified from second-generation libraries of N-acylated L-homoserine lactones.

Mattmann Margrith E ME Shipway Patrick M PM Heth Nicole J NJ Blackwell Helen E HE

Chembiochem : a European journal of chemical biology 20110301 6

Bacteria can coordinate group behavior using chemical signals in a process called quorum sensing (QS). The QS system in the opportunistic pathogen Pseudomonas aeruginosa is largely governed by the LasR receptor and its cognate chemical signal, N-(3-oxo)-dodecanoyl L-homoserine lactone (OdDHL). LasR also appears to share this signal with an orphan LuxR-type receptor in P. aeruginosa, termed QscR, which represses LasR activity. Non-native molecules that modulate QscR would represent valuable tools ...[more]

PMID: 21365734

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Project description:Quorum sensing (QS) is a process by which bacteria use low-molecular-weight signaling molecules (or autoinducers) to assess their local population densities and alter gene expression levels at high cell numbers. Many Gram-negative bacteria use N-acyl L-homoserine lactones (AHLs) with aliphatic acyl groups as signaling molecules for QS. However, bacteria that utilize AHLs with aroyl acyl groups have been recently discovered; they include the metabolically versatile soil bacterium Rhodopseudomonas palustris, which uses p-coumaroyl HL (p-cAHL) as its QS signal. This autoinducer is especially unusual because its acyl group is believed to originate from a monolignol (i.e., p-coumarate) produced exogenously by plants in the R. palustris environment, rather than through the endogenous fatty acid biosynthesis pathway like other native AHLs. As such, p-cAHL could signal not only bacterial density, but also the availability of an exogenous plant-derived substrate and might even constitute an interkingdom signal. Like other Gram-negative bacteria, QS in R. palustris is controlled by the p-cAHL signal binding its cognate LuxR-type receptor, RpaR. We sought to determine if non-native aroyl HLs (ArHLs) could potentially activate or inhibit RpaR in R. palustris, and thereby modulate QS in this bacterium. Herein, we report the testing of a set of synthetic ArHLs for RpaR agonism and antagonism by using a R. palustris reporter strain. Several potent non-native RpaR agonists and antagonists were identified. Additionally, the screening data revealed that lower concentrations of ArHL are required to strongly agonize RpaR than to antagonize it. Structure-activity relationship analyses of the active ArHLs indicated that potent RpaR agonists tend to have sterically small substituents on their aryl groups, most notably in the ortho position. In turn, the most potent RpaR antagonists were based on either the phenylpropionyl HL (PPHL) or the phenoxyacetyl HL (POHL) scaffold, and many contained an electron-withdrawing group at either the meta or para positions of the aryl ring. To our knowledge, the compounds reported herein represent the first abiotic chemical modulators of RpaR, and more generally, the first abiotic ligands capable of intercepting QS in bacteria that utilize native ArHL signals. In view of the origins of the p-cAHL signal in R. palustris, the largely unknown role of QS in this bacterium, and R. palustris' unique environmental lifestyles, we anticipate that these compounds could be valuable as chemical probes to study QS in R. palustris in a range of fundamental and applied contexts.

Project description:BackgroundSchistosomiasis is a prevalent neglected tropical disease that affects approximately 300 million people worldwide. Its treatment is through a single class chemotherapy, praziquantel. Concerns surrounding the emergence of praziquantel insensitivity have led to a need for developing novel anthelmintics.Methodology/principle findingsThrough evaluating and screening fourteen compounds (initially developed for anti-cancer and anti-viral projects) against Schistosoma mansoni, one of three species responsible for most cases of human schistosomiasis, a racemic N-acyl homoserine (1) demonstrated good efficacy against all intra mammalian lifecycle stages including schistosomula (EC50 = 4.7 μM), juvenile worms (EC50 = 4.3 μM) and adult worms (EC50 = 8.3 μM). To begin exploring structural activity relationships, a further 8 analogues of this compound were generated, including individual (R)- and (S)- enantiomers. Upon anti-schistosomal screening of these analogues, the (R)- enantiomer retained activity, whereas the (S)- lost activity. Furthermore, modification of the lactone ring to a thiolactone ring (3) improved potency against schistosomula (EC50 = 2.1 μM), juvenile worms (EC50 = 0.5 μM) and adult worms (EC50 = 4.8 μM). As the effective racemic parent compound is structurally similar to quorum sensing signaling peptides used by bacteria, further evaluation of its effect (along with its stereoisomers and the thiolactone analogues) against Gram+ (Staphylococcus aureus) and Gram- (Escherichia coli) species was conducted. While some activity was observed against both Gram+ and Gram- bacteria species for the racemic compound 1 (MIC 125 mg/L), the (R) stereoisomer had better activity (125 mg/L) than the (S) (>125mg/L). However, the greatest antimicrobial activity (MIC 31.25 mg/L against S. aureus) was observed for the thiolactone containing analogue (3).Conclusion/significanceTo the best of our knowledge, this is the first demonstration that N-Acyl homoserines exhibit anthelmintic activities. Furthermore, their additional action on Gram+ bacteria opens a new avenue for exploring these molecules more broadly as part of future anti-infective initiatives.

Dataset Information

Potent and selective synthetic modulators of a quorum sensing repressor in Pseudomonas aeruginosa identified from second-generation libraries of N-acylated L-homoserine lactones.

Publications

Potent and selective synthetic modulators of a quorum sensing repressor in Pseudomonas aeruginosa identified from second-generation libraries of N-acylated L-homoserine lactones.

Similar Datasets

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