Deploying Microbial Synthesis for Halogenating and Diversifying Medicinal Alkaloid Scaffolds

Abstract

Plants produce some of the most potent therapeutics and have been used for thousands of years to treat human diseases. Today, many medicinal natural products are still extracted from source plants at scale as their complexity precludes total synthesis from bulk chemicals. However, extraction from plants can be an unreliable and lowyielding source for human therapeutics, making the supply chain for some of these life-saving medicines expensive and unstable. There has therefore been significant interest in refactoring these plant pathways in genetically tractable microbes, which grow more reliably and where the plant pathways can be more easily engineered to improve the titer, rate and yield of medicinal natural products. In addition, refactoring plant biosynthetic pathways in microbes also offers the possibility to explore new-tonature chemistry more systematically, and thereby help expand the chemical space that can be probed for drugs as well as enable the study of pharmacological properties of such new-to-nature chemistry. This perspective will review the recent progress toward heterologous production of plant medicinal alkaloids in microbial systems. In particular, we focus on the refactoring of halogenated alkaloids in yeast, which has created an unprecedented opportunity for biosynthesis of previously inaccessible new-to-nature variants of the natural alkaloid scaffolds.

Antibiofilm and Antimicrobial Activities of Chloroindoles Against Uropathogenic Escherichia coli

“…3D-QSAR analysis indicated that substitutions at the fourth and fifth positions of the indole moiety increased antimicrobial activity and that substitution at the seventh position was unfavorable ( Figure 7B ). These positional effects may be due to the influence halogen substitution has on the electronic structure of the indole scaffold, such as on the σ-hole region of low electron density and the dipole that permits binding to lone pair acceptors and donors of the receptors altering ligand binding sterics with its bulk ( Bradley et al, 2020 ). ADME profiling of 4CI, 5CI, and 5CMI predicted them to be non-carcinogenic to mice, to have minimal acute fish toxicities, and not to violate Lipinski’s rule of five ( Supplementary Table S6 ).…”

Applications of Virtual Screening in Bioprospecting: Facts, Shifts, and Perspectives to Explore the Chemo-Structural Diversity of Natural Products

“…Natural products are chemically complex and differ from synthetic compounds in different aspects; as an example, these structures contain a high percentage of oxygen as well as a larger fraction of sp3-hybridized atoms and chiral centers (Lee and Schneider, 2001 ; Feher and Schmidt, 2003 ; Rodrigues et al, 2016 ), and their chemical space is highly diverse, containing different structural scaffolds, when compared with synthetic compound libraries (Chen et al, 2018 ). Due to their unique features, their structures can provide an innovative solution for the design and synthesis of new bioactive compounds (Kumar et al, 2017 ; Silva et al, 2019 ; Bradley et al, 2020 ; Morais et al, 2020 ).…”

Metabolic engineering for plant natural products biosynthesis: new procedures, concrete achievements and remaining limits

“…While scarce in yeast, such modications have been already reported in plants through a direct in planta engineering of NP synthesis. 37 Taking advantage of N. benthamiana transient transformation efficiency, Calgaro-Kozina and co-workers transferred the glucosinolate biosynthetic pathway and expanded upon the diversity of the produced biopesticides. 38 Glucosinolate are amino acid-derived compounds with a sulfur bound to glucose and the nitrogen bound to sulfate notably produced in crucifers.…”