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 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) 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 (EC 50 = 4.7 μM), juvenile worms (EC 50 = 4.3 μM) and adult worms (EC 50 = 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 (EC 50 = 2.1 μM), juvenile worms (EC 50 = 0.5 μM) and adult worms (EC 50 = 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/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.

Using ChEMBL to Complement Schistosome Drug Discovery

“…The ex vivo anti-schistosomal activity of those compounds were initially tested on the larval schistosomula stage using a high content imaging platform [ 24 , 34 , 50 ] ( Figure 2 ). At the highest concentration tested (50 µM), 37 compounds showed anti-schistosomal activity following 72 h co-incubation ( Figure 2 a).…”

“…Ex vivo schistosomula compound screens were performed as previously described [ 48 , 49 , 50 , 51 ]. Briefly, mechanically transformed schistosomula were automatically dispensed into a 384-well plate (120 parasite/well).…”

“…Adult worms were recovered by hepatic portal vein perfusion and prepared as previously described [ 34 , 49 , 50 ]. For this specific study, adult worms (1 worm pair/1 mL of adult worm media) were dosed with 10 µM of each compound (in 0.1% DMSO).…”

Small Molecule Ligands of the BET-like Bromodomain, SmBRD3, Affect Schistosoma mansoni Survival, Oviposition, and Development

“…S. mansoni schistosomula were obtained by mechanical transformation from cercariae as previously described, distributed in 384-well tissue culture plates (PerkinElmer, catalogue number 6007460) at 120 parasites/well and dosed with the selected compounds as previously reported. − For this study, each compound (as 10 mM DMSO stock solution) was initially tested at two concentration points (20 and 10 μM final concentration, in duplicates) in at least four independent screens ( Z ′ scores above 0.35) . Each screen contained both positive (10 μM auranofin (AUR) in 0.625% DMSO) and negative (0.625% DMSO) controls.…”

Angiotensin-Converting Enzyme Inhibitor “Lisinopril” Antagonizes Hepatic TGF-β1, improving Hepatic Fibrosis Caused by Experimental Schistosomiasis mansoni

“…For this reason, anti-fibrotic chemotherapy as an adjuvant to PZQ could be a possible therapeutic option. Certainly, PZQ was extensively studied during the foregoing decades, either as a monotherapeutic anti-schistosome treatment or in combination with other medicinal agents, using the usual investigative parameters in terms of oogram study, tissue egg load, hepatic granuloma number & diameter and performing the commonly used staining techniques as Haematoxylin & Eosin and Masson trichrome staining (Mehlhorn et al, 1981;Giboda et al, 1992;Dupré et al, 1999;Hussein et al, 2017;Whiteland et al, 2020). In a trial to reflect the extent of success of the used therapies in achieving a satisfactory degree of cure, the previously mentioned studies documented variable information, in addition to special considerations related to the tissue type of hepatic granuloma and whether they were cellular, fibrous or fibro-cellular.…”