New antiplasmodial compounds discovered by High Throughput Screening (HTS) of a collection of microbial natural extracts

Malaria is a widespread disease in tropical and subtropical regions and an estimated 3.2 billion people are at the risk of suffering it, with 0.5 – 1 million deaths reported in 2014. Due to the low variety and structural diversity of antimalarial drugs currently available in the clinic and the increasing number of cases of resistance against these drugs, there is an urgent need to find new treatments with novel modes of action. Microbial natural products have not been yet exhaustively explored in the search for new antiparasitic drugs, especially in the case of malaria, and therefore they offer a valuable source for the discovery of new and interesting hits [1]. With the aim of finding new drugable natural products with antimalarial properties, a subset of 22,000 samples of the MEDINA natural product extracts collection, one of the largest natural products libraries harbouring more than 130,000 microbial extracts, was screened using a phenotypic HTS based on measurements of Plasmodium falciparum lactate dehydrogenase [2]. Active hits from this test were subjected to chemical dereplication using LC-LRMS, LC-HRMS and LC-NMR in the off-line mode in order to discard samples containing known antimalarial and/or cytotoxic molecules [3]. Hits containing potentially new molecules were re-fermented at 1L scale and the compounds responsible for the bioactivity of the extracts were isolated following a bioassay-guided process. Several new molecules with antimalarial activity in the micromolar range were obtained using this approach, including the naphthoquinone lasionectrin [4], the betaine lipid MDN-0104 [5], a new member of the pepstatin family, pepstatin K [2], and two cyclic hexapeptides. Additionally, a new polycyclic xanthone structurally related to xantholipin [6] and Sch 54445 [7] with an IC₅₀ of 9 nM against P. falciparum 3D7 was also obtained. The approach used in this work confirms once more that microbial natural products continue to be a rich and underexploited source of novel molecules that might lead to the discovery of new and interesting drugs.

Acknowledgements: This work was supported by the Junta de Andalucía [BIO-199, P09-CVI- 5367], the VI Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica 2008 – 2011, Instituto de Salud Carlos III-Subdirección General de Redes y Centros de Investigación Cooperativa-Red de Investigación Cooperativa en Enfermedades Tropicales (RICET FIS Network: RD12/0018/0017), the Plan Nacional (SAF2013 – 48999-R), the FEDER funds from the EU and the PARAMET network (FP7-PEOPLE-2011-ITN. GA290080).

Keywords: Malaria, Plasmodium falciparum, HTS, microbial extracts, natural products.

References:

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No conflict of interest has been declared by the author(s).