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A biosynthetic platform for antimalarial drug discovery

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Antimicrobial Agents and Chemotherapy-2020-Wilkinson-e02129-19.full.pdfPublished version1.24 MBAdobe PDFView/Open
Title: A biosynthetic platform for antimalarial drug discovery
Authors: Wilkinson, MD
Lai, H-E
Freemont, PS
Baum, J
Item Type: Journal Article
Abstract: Advances in synthetic biology have enabled production of a variety of compounds using bacteria as a vehicle for complex compound biosynthesis. Violacein, a naturally occurring indole pigment with antibiotic properties, can be biosynthetically engineered in Escherichia coli expressing its non-native synthesis pathway. To explore whether this synthetic biosynthesis platform could be used for drug discovery, here we have screened bacterially-derived violacein against the main causative agent of human malaria, Plasmodium falciparum. We show the antiparasitic activity of bacterially-derived violacein against the P. falciparum 3D7 laboratory reference strain as well as drug-sensitive and resistant patient isolates, confirming the potential utility of this drug as an antimalarial. We then screen a biosynthetic series of violacein derivatives against P. falciparum growth. The demonstrated varied activity of each derivative against asexual parasite growth points to potential for further development of violacein as an antimalarial. Towards defining its mode of action, we show that biosynthetic violacein affects the parasite actin cytoskeleton, resulting in an accumulation of actin signal that is independent of actin polymerization. This activity points to a target that modulates actin behaviour in the cell either in terms of its regulation or its folding. More broadly, our data show that bacterial synthetic biosynthesis could become a suitable platform for antimalarial drug discovery with potential applications in future high-throughput drug screening with otherwise chemically-intractable natural products.
Issue Date: May-2020
Date of Acceptance: 23-Feb-2020
URI: http://hdl.handle.net/10044/1/77366
DOI: 10.1128/aac.02129-19
ISSN: 0066-4804
Publisher: American Society for Microbiology
Start Page: 1
End Page: 9
Journal / Book Title: Antimicrobial Agents and Chemotherapy
Volume: 64
Issue: 5
Copyright Statement: © 2020 Wilkinson et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/).
Sponsor/Funder: Wellcome Trust
Wellcome Trust
Medical Research Council (MRC)
Engineering & Physical Science Research Council (EPSRC)
Funder's Grant Number: 100993/Z/13/Z
100993/Z/13/Z
MR/N012275/1
EP/L011573/1
Keywords: Science & Technology
Life Sciences & Biomedicine
Microbiology
Pharmacology & Pharmacy
violacein
drug discovery
antimalarial
drug resistance
synthetic biology
CELL-DEATH
IN-VITRO
VIOLACEIN
MALARIA
MECHANISM
antimalarial
drug discovery
drug resistance
synthetic biology
violacein
0605 Microbiology
1108 Medical Microbiology
1115 Pharmacology and Pharmaceutical Sciences
Microbiology
Publication Status: Published online
Open Access location: http://aac.asm.org/cgi/pmidlookup?view=long&pmid=32152076
Online Publication Date: 2020-04-21
Appears in Collections:Department of Infectious Diseases
Faculty of Natural Sciences