Quorum sensing n-acyl homoserine lactones are a new class of anti-schistosomal

Abstract

Background Schistosomiasis is a prevalent neglected tropical disease that affects approximately 300 mil-lion 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) 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 struc-tural 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 ana-logues) 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/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.