Quorum sensing N-Acyl homoserine lactones are a new class of anti-schistosomal
Authors: Whiteland H , Crusco A , Bloemberg LW , Tibble-Howlings J , Forde-Thomas J , Coghlan A , Murphy P. J , Hoffmann KF 
Published: July 2020

Background

Schistosomiasis 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 findings

Through evaluating and screening fourteen compounds (initially developed for anti-cancer and anti-viral projects) againstSchistosoma 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 active 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 compound1(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 againstS. aureus) was observed for the thiolactone containing analogue (3).

Conclusion/Significance

To 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.

Author Summary

Schistosomiasis, caused by infection with blood fluke schistosomes, is a neglected tropical disease that negatively impacts the lives of approximately 300 million people worldwide. In the absence of a vaccine, it is currently controlled by a single drug, Praziquantel (PZQ). Although incredibly valuable in controlling disease burden, PZQ-mediated chemotherapy is ineffective against juvenile worms and may not be sustainable should resistance develop. The need to identify an alternative or combinatorial drug is, therefore, a priority in contributing to the control of this parasitic disease into the 21stcentury. In this study, we have identified a new class of anthelmintic, N-acyl homoserine lactones, which are normally used by bacteria for quorum sensing and population density control. The tested N-acyl homoserine lactones were active against all intra-human schistosome lifecycle stages, in particular, when a thiolactone modification to the core N-acyl homoserine ring was made. Interestingly, these N-acyl homoserine lactones also displayed antimicrobial activities against Gram+Staphylococcus aureus. By demonstrating broad activities against schistosomes and bacteria exemplars, this study identified a potential route for the further development of a new anti-infective class.