A Biosynthetic Platform for Antimalarial Drug Discovery.

Antimicrobial Agents and Chemotherapy
Mark D WilkinsonJake Baum

Abstract

Advances in synthetic biology have enabled the 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 nonnative 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 agent. We then screen a biosynthetic series of violacein derivatives against P. falciparum growth. The varied activity of each derivative against asexual parasite growth points to the need to further develop 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 poin...Continue Reading

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Citations

Mar 11, 2021·ACS Infectious Diseases·Tatyana Almeida TavellaFabio Trindade Maranhão-Costa
Mar 13, 2021·Journal of Biological Engineering·Seong Yeol ChoiRobert J Mitchell
Mar 19, 2021·Critical Reviews in Biotechnology·HyunA ParkKwon-Young Choi
Oct 15, 2021·ACS Chemical Biology·Hung-En LaiPaul S Freemont

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Methods Mentioned

BETA
flow cytometry

Software Mentioned

Sigma
EpiDemic Plugin
ImageJ
Biosyn
Vio
GraphPad Prism

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