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A key n??* Interaction in N-acyl homoserine lactones.

ABSTRACT: Many Gram-negative bacteria employ N-acyl homoserine lactones (AHLs) as signal molecules for quorum sensing. The binding of AHLs to their target LuxR-type receptor proteins can effect changes in growth, virulence, and other phenotypes. LuxR-type receptors therefore present attractive pharmaceutical targets for control of bacterial pathogenesis. Here, we present X-ray crystallographic and computational evidence that the conformation of free AHLs is biased away from the conformation observed when bound to their cognate receptor due to the influence of an n??* interaction. In this n??* interaction, the p-type lone pair (n) of the N-acyl oxygen overlaps with the ?* orbital of the lactone carbonyl group. This overlap results in the release of approximately 0.64 kcal/mol of energy. We also show that this interaction can be attenuated by installing electron-withdrawing groups on the N-acyl chain. Modulating this previously unappreciated interaction could present a new avenue toward effective inhibitors of bacterial quorum sensing.

SUBMITTER: Newberry RW

PROVIDER: S-EPMC4219647 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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A key n→π* Interaction in N-acyl homoserine lactones.

Newberry Robert W RW Raines Ronald T RT

ACS chemical biology 20140226 4

Many Gram-negative bacteria employ N-acyl homoserine lactones (AHLs) as signal molecules for quorum sensing. The binding of AHLs to their target LuxR-type receptor proteins can effect changes in growth, virulence, and other phenotypes. LuxR-type receptors therefore present attractive pharmaceutical targets for control of bacterial pathogenesis. Here, we present X-ray crystallographic and computational evidence that the conformation of free AHLs is biased away from the conformation observed when ...[more]

PMID: 24556113

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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.

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A key n??* Interaction in N-acyl homoserine lactones.

Publications

A key n→π* Interaction in N-acyl homoserine lactones.

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