Harnessing biocatalysis as a green tool in antibiotic synthesis and discovery

Abstract

Biocatalysis offers a sustainable approach to drug synthesis, leveraging the high selectivity and efficiency of enzymes. This review explores the application of biocatalysis in the early-stage synthesis of antimicrobial compounds, emphasizing its advantages over traditional chemical methods. We discuss various biocatalysts, including enzymes and whole-cell systems, and their role in the selective functionalization and preparation of antimicrobials and antibacterial building blocks. The review underscores the potential of biocatalysis to advance the development of new antibiotics and suggests directions and potential applications of enzymes in drug development.

Fig. 1. Chemoenzymatic synthesis of a vancomycin derivative 2 with the oxygenase enzymes.

Fig. 2. (a) Laccase-assisted iodination of gallic acid; (b) biocatalytic synthesis of dihydroxyequol using monooxygenase enzymes; (c) biotransformation process of p-aminobenzoic acid to p-nitrobenzoic acid.

Fig. 3. (a) Remote hydroxylation by oxygenase enzymes GetF and Getl; (b) enzymatic chlorination with halogenase FasV; (c) one-pot biocatalytic transformation of d-glucose to 2-deoxy-scyllo-inosose; (d) biotransformation of resveratrol and pterostilbene with the secretome of B. cinerea; (e) laccase-immobilized for enzymatic degradation of oxytetracycline in the environment.

Fig. 4. Enzymatic glycosylation of vancomycin aglycon (27) by glycosyltransferases GtfE and GtfD.

Fig. 5. (a) Enzymatic synthesis of monoterpene O-glycosides by glycosyltransferases; (b) chemoenzymatic synthesis of trehalosamine derivatives via trehalose synthase-catalysed glycosylation; (c) chemoenzymatic transglycosylation using glycosyltransferases.

Fig. 6. (a) Enzymatic synthesis of amikacin derivatives using transferases GenN; (b) enzymatic synthesis of arsinothricin (42); (c) enzymatic synthesis of myxin (45).

Fig. 7. Chemoenzymatic synthesis of daptomycin derivatives by prenyltransferase CdpNPT.

Fig. 8. Enzymatic synthesis of sialylated lactuloses via sialyltransferases PmST1 and Pd26ST.

Fig. 9. (a) Lipase-catalysed synthesis of β-phosphonomalononitriles; (b) lipase-catalysed transesterification of alcohol and kinetic resolution; (c) transesterification of umbelliferone with lipase; (d) biocatalytic synthesis of disulphide using lipase; (e) lipase-catalysed regioselective acylation of andrographolide.

Fig. 10. Chemoenzymatic synthesis of bicyclic chimera 66 by the proteolytic enzyme ficin.

Fig. 11. (a) Biocatalytic synthesis of d-p-hydroxyphenylglycine by d-hydantoinase and d-carbamoylase; (b) enzymatic synthesis of cephalexin catalysed by penicillin G acylase; (c) enzymatic reaction catalysed by KcPGA to degrade quorum sensing signal molecules.

Fig. 12. (a) Biocatalytic synthesis of bicyclic β-lactams tandem enzymes Ccr-CMPS-CarA; (b) enzymatic synthesis of cefazolin by cephalosporin-acid synthetase.