Late-stage diversification of bacterial natural products through biocatalysis

Abstract

Bacterial natural products (BNPs) are very important sources of leads for drug development and chemical novelty. The possibility to perform late-stage diversification of BNPs using biocatalysis is an attractive alternative route other than total chemical synthesis or metal complexation reactions. Although biocatalysis is gaining popularity as a green chemistry methodology, a vast majority of orphan sequenced genomic data related to metabolic pathways for BNP biosynthesis and its tailoring enzymes are underexplored. In this review, we report a systematic overview of biotransformations of 21 molecules, which include derivatization by halogenation, esterification, reduction, oxidation, alkylation and nitration reactions, as well as degradation products as their sub-derivatives. These BNPs were grouped based on their biological activities into antibacterial (5), antifungal (5), anticancer (5), immunosuppressive (2) and quorum sensing modulating (4) compounds. This study summarized 73 derivatives and 16 degradation sub-derivatives originating from 12 BNPs. The highest number of biocatalytic reactions was observed for drugs that are already in clinical use: 28 reactions for the antibacterial drug vancomycin, followed by 18 reactions reported for the immunosuppressive drug rapamycin. The most common biocatalysts include oxidoreductases, transferases, lipases, isomerases and haloperoxidases. This review highlights biocatalytic routes for the late-stage diversification reactions of BNPs, which potentially help to recognize the structural optimizations of bioactive scaffolds for the generation of new biomolecules, eventually leading to drug development.

Keywords: bacterial natural products; bioactive molecules; biocatalysis; biotransformation; enzymatic diversification; late-stage modification.

FIGURE 1

Selected bacterial natural products grouped by their biological activity: (Ai–v) antibiotics, (Bi–v) antifungals, (Ci–v) anticancer compounds, (Di–ii) immunosuppressants, and (Ei–iv) quorum sensing modulators. Fully colored shapes denote known and described diversification reactions achieved through biocatalysis and shown in this review paper, and empty shapes denote potential places for biocatalytic transformations. The overlapping shapes indicate that multiple diversification reactions are possible on a specific functional group.

FIGURE 2

Enzymatic derivatization of vancomycin. (A) Enzymatic incorporations of galactose by β-1,4-galactosyltransferase and (B) sialic acid by α-2,3-sialyl transferase into vancomycin and pseudo-vancomycin (Oh et al., 2011). (C) Synthesis and hydrolysis of various vancomycin esters by Amano LPL-80 lipase from Pseudomonas sp. (Adamczyk et al., 1998; Thayer and Wong, 2006). (D) One-pot enzymatic glycosylation of vancomycin aglycon using glycosyltransferase (GtfE) (Thayer and Wong, 2006).

FIGURE 3

Biocatalytic reactions of Doxorubicin. (A) Acylation by lipase from M. javanicus using vinyl butyrate (Altreuter et al., 2002). (B) Acylation by lipase from M. javanicus using 2-thiophene acetic acid vinyl ester (Altreuter et al., 2002), (C) carbonyl reduction by carbonyl reductase 1 (CBR1) and aldo-keto reductase 1C3 (AKR1C3) (Piska et al., 2021).

FIGURE 4

Enzymatic esterification of rapamycin at 42-hydroxyl position in the presence of one of the following lipases: Novozym 435, lipase PS-C “Amano” II, lipase PS-D “Amano” I and (A) vinyl acetate, vinyl propionate, vinyl 1-chloroacetate, vinyl crotonate, vinyl benzoate and vinyl decanoate (Gu et al., 2005) (B) succinic anhydride in toluene (Gu et al., 2005), (C) divinyl adipate in TBME in the first step and acetonitrile in the second step (Gu et al., 2005). Biocatalytic synthesis of temsirolimus using (D) cyclic methylborate protected vinyl ester in the first step, and alcoholic solvents such as MeOH, EtOH, 2-methylpentane-2 or -5-diol for the deprotection in the second step (Gu et al., 2005), (E) ketal-protected vinyl esters in the first step, and a subsequent acid-catalyzed deprotection (Ju et al., 2015). (F) Glycosylation of rapamycin using glycosyltransferases BsGT-1 and UDP-Glc as the sugar donor with three possible products (Zhang et al., 2020). These reactions yielded 18 novel rapamycin derivatives.

FIGURE 5

Enzymatic modification of 1-hydroxyphenazine through the use of a monooxygenase and/or methyltransferase. (A) Enzymatic methylation of 1-hydroxyphenazine using methyltransferase LphzM and S-adenosyl methionine (SAM) in HEPES (N-(2-hydroxyethyl)-1-piperazine-N’-(2-ethanesulfonic acid) buffer. (B) Enzymatic oxidation of 1-hydroxyphenazine using N-monooxygenase NaphzNO1 in the presence of nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FAD). (C) Enzymatic oxidation of 1-hydroxyphenazine using N-monooxygenase NaphzNO1 followed by methylation using methyltransferase LphzM in HEPES buffer (Wan et al., 2022).