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Paenidigyamycin A, Potent Antiparasitic Imidazole Alkaloid from the Ghanaian Paenibacillus Sp

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Paenidigyamycin A, Potent Antiparasitic Imidazole Alkaloid from the Ghanaian Paenibacillus Sp marine drugs Article Paenidigyamycin A, Potent Antiparasitic Imidazole Alkaloid from the Ghanaian Paenibacillus sp. DE2SH Enoch Osei 1,†, Samuel Kwain 1,†, Gilbert Tetevi Mawuli 1, Abraham Kwabena Anang 2, Kofi Baffour-Awuah Owusu 2, Mustafa Camas 3, Anil Sazak Camas 3, Mitsuko Ohashi 4, Cristina-Nicoleta Alexandru-Crivac 5, Hai Deng 5, Marcel Jaspars 5 and Kwaku Kyeremeh 1,* 1 Marine and Plant Research Laboratory of Ghana, Department of Chemistry, School of Physical and Mathematical Sciences, University of Ghana, P.O. Box LG 56, Legon-Accra, Ghana; kofi[email protected] (E.O.); [email protected] (S.K.); [email protected] (G.T.M.) 2 Department of Parasitology, Noguchi Memorial Institute for Medical Research, University of Ghana, P.O. Box LG 581, Legon-Accra, Ghana; [email protected] (A.K.A.); [email protected] (K.B.-A.O.) 3 Department of Bioengineering, Munzur University, 62000 Tunceli, Turkey; [email protected] (M.C.); [email protected] (A.S.C.) 4 Section of Environmental Parasitology, Tokyo Medical and Dental University, Tokyo 113-8510, Japan; [email protected] 5 Marine Biodiscovery Centre, Department of Chemistry, University of Aberdeen, Old Aberdeen, AB24 3UE Scotland, UK; [email protected] (C.-N.A.-C.); [email protected] (H.D.); [email protected] (M.J.) * Correspondence: [email protected]; Tel.: +233-20-789-1320 † These authors contributed equally to this paper. Received: 13 November 2018; Accepted: 17 December 2018; Published: 24 December 2018 Abstract: A new alkaloid paenidigyamycin A (1) was obtained from the novel Ghanaian Paenibacillus sp. isolated from the mangrove rhizosphere soils of the Pterocarpus santalinoides tree growing in the wetlands of the Digya National Park, Ghana. Compound 1 was isolated on HPLC at tR = 37.0 min and its structure determined by MS, 1D, and 2D-NMR data. When tested against L. major, 1 (IC50 0.75 µM) was just as effective as amphotericin B (IC50 0.31 µM). Against L. donovani, 1 (IC50 7.02 µM) was twenty-two times less active than amphotericin B (IC50 0.32 µM), reinforcing the unique effectiveness of 1 against L. major. For T. brucei brucei, 1 (IC50 0.78 µM) was ten times more active than the laboratory standard Coptis japonica (IC50 8.20 µM). The IC50 of 9.08 µM for 1 against P. falciparum 3d7 compared to artesunate (IC50 36 nM) was not strong, but this result suggests the possibility of using the paenidigyamycin scaffold for the development of potent antimalarial drugs. Against cercariae, 1 showed high anticercaricidal activity compared to artesunate. The minimal lethal concentration (MLC) and minimal effective concentration (MEC) of the compound were 25 and 6.25 µM, respectively, while artesunate was needed in higher quantities to produce such results. However, 1 (IC50 > 100 µM) was not active against T. mobilensis. Keywords: paenidigyamycin; plasmodium; trypanosome; leishmania; trichomonas; schistosome 1. Introduction Sub-Sahara Africa (SSA) is burdened with a high incidence of parasitic infections, including schistosomiasis, trypanosomiasis, trichomoniasis, and leishmaniasis [1–3]. Currently, there is a rapid widespread development of resistance to prescription drugs for these parasitic neglected tropical diseases (pNTDs) [4–8]. The available number of drugs for treatment is exceptionally low and each of these has been under prescription for periods of no less than 30 years [9]. A rough estimate of Mar. Drugs 2019, 17, 9; doi:10.3390/md17010009 www.mdpi.com/journal/marinedrugs Mar. Drugs 2019, 17, 9 2 of 13 Mar. Drugs 2018, 16, x FOR PEER REVIEW 2 of 14 averagethe average of the of theprescription prescription periods periods from from time time of ofdiscovery discovery to-date to-date for for the the top top 10 10 antiparasitics, including praziquantel or oxamniquine,oxamniquine, amphotericine,amphotericine, pentavalent anti antimonials,monials, paromomycin, miltefosine, pentamidine, pentamidine, fluconazole fluconazole or or itraconazo itraconazole,le, melarsoprol, melarsoprol, eflornithine, eflornithine, and andnifurtimox nifurtimox that arethat currently are currently prescribed prescribed in the in clinic the clinicis about is about56 years. 56 Furthermore, years. Furthermore, pNTD drugs pNTD only drugs treat only specific treat stagesspecific of stages parasite of parasite development, development, thereby thereby complicating complicating the thetreatment treatment routines routines for for patients patients and preventing complete parasite removal from the body [10,11]. [10,11]. Due to their long time prevalence in SSA, pNTDs have parasites and vectors whose genomes and lifecycles have evolved to assure their resilience and persistence [4]. [4]. Vectors responsible for pNTD transmissions are difficultdifficult to control and there is a huge debate concerning attempts to completely annihilate them [12]. [12]. Clearly, Clearly, there is an urgent need to discover new scaffolds that would provide a platform for the development of future antiparasitics against pNTDs [[13].13]. Microbia Microbiall natural natural products provide the largest chemical and biological diversity in any drug discovery screening program compared to other natural sources, like plants and invertebrates, with the re resupplysupply problems mostly overcome with large-scale fermentation and and heterologous heterologous expression expression [9,14–16] [9,14–16.]. Extreme Extreme un- un- or or underexplored underexplored environments environments in SSAin SSA harbor harbor novel novel microbes microbes which, which, through through millions millions of of years years of of evolution, evolution, have have evolved evolved genomes that express chemically diverse molecules that could act as future drug leads for pNTDs and other diseases [[17,18].17,18]. In the last four years,years, we havehave collectedcollected severalseveral soils and sedimentssediments from unexploredunexplored unique environments in the Ghanaian Western, Volta, and Brong Ahafo Regional wetlands. From these samples, we have isolated many cultivable strains of microbes, most of which give extracts which show antiparasitic activity. Herein, wewe reportreport on on the the isolation isolation and and purification purification of the of Ghanaian the GhanaianPaenibacillus Paenibacillussp. strain sp. DE2SH strain (GenBankDE2SH (GenBank Accession Accession Number: Number: MH091697) MH091697) from mangrove from mangrove rhizosphere rhizosphere soils collected soils fromcollected the Digya from theNational Digya Park National in the Park Brong in Ahafothe Brong Regional Ahafo wetlands Regional of wetlands Ghana. Culture of Ghana. of this Culture strain of at this 28 ◦ C,strain 220 at rpm, 28 °C,in ISP2 220rpm, media in ISP2 at pH media 5.5 produced at pH 5.5 aproduced crude extract a crude which extract possessed which possesse antiparasiticd antiparasitic activity activity against againsttrypanosomes, trypanosomes, schistosomes, schistosomes, leishmania, leishmania, and plasmodium. and plasmodium. Chemical Chemical profiling profiling of this of extract this extract using usinghigh resolution high resolution electrospray electrospray ionization liquidionization chromatography liquid chromatography mass spectrometry mass (HRESI-LC-MS) spectrometry (HRESI-LC-MS)and nuclear magnetic and nuclear resonance magnetic spectroscopy resonance (NMR) spectroscopy showed (NMR) the presence showed of the an alkaloidpresencewhich of an wealkaloid have which named we paenidigyamycin have named paenidigyamycin (Figure1). Solvent (Figure partitioning, 1). Solvent Sephadex partitioning, LH-20 Sephadex size exclusion LH-20 sizechromatography, exclusion chromatography, and HPLC yielded and HPLC the potent yielded antiparasitic, the potent antiparasitic, paenidigyamycin paenidigyamycin A (1) (1.6 mg/L). A (1) The(1.6 structuremg/L). The ofthis structure compound of this was compound determined was using determined a combination using of 1D-a combination and 2D-NMR of techniques 1D- and with2D-NMR HRESI-LC-MS techniques data. with HRESI-LC-MS data. 4'' 5'' 3'' 13 14 12 6'' 2'' 1'' 11 9' 10 8' 6 3 N 1' N 7' 4 2 2' 5' 4' 5 N 1 3' N 7 6' 8 10' 9 11' 1' 2' 6' 12' 14' 13' 3' 5' 4' FigureFigure 1. Structure 1. Structure of the ofimidazole-based the imidazole-based alkaloid alkaloid paenidigyamycin paenidigyamycin A (1) isolated A (1) isolated from Paenibacillus from Paenibacillussp. DE2SH. sp. DE2SH. Mar. Drugs 2019, 17, 9 3 of 13 2. Results and Discussion 2.1. SedimentMar. SampleDrugs 2018 Collection, 16, x FOR PEER Sites REVIEW 3 of 14 The Ghanaian Paenibacillus sp. strain DE2SH (Supplementary Figure S1) was isolated from the 2. Results and Discussion mangrove rhizosphere soils of the Pterocarpus santalinoides tree growing in the wetland areas of the ◦ 0 ◦ 0 Digya National2.1. Sediment Park inSample the BrongCollection Ahafo Sites Region of Ghana (coordinates: 7 12 17.46”N and 0 05 35.01”E). This area has several patches of mangroves which are associated with the biggest reservoir man-made The Ghanaian Paenibacillus sp. strain DE2SH (Supplementary Figure S1) was isolated from the lake, Lakemangrove Volta. Water rhizosphere from thesoils tributaries of the Pterocarpus of the santalinoides Volta ensures tree growing that the in area the occupiedwetland areas by of this the tree is covered withDigya water National throughout Park in thethe year. Brong Lake Ahaf Voltao Region is an openof Ghana lake (coordinates: that is connected 7°12′17.46 to the″N seaand at the Ada Foah0°05 Basin,′35.01 which″E). This in itselfarea has is aseveral very dramaticpatches
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