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Old and new glycopeptide antibiotics: From product to gene and back in the post-genomic era |
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| Authors: | Giorgia Letizia Marcone Elisa Binda Francesca Berini Flavia Marinelli |
| Institution: | 1. Department of Biotechnology and Life Sciences, University of Insubria, via J.H. Dunant 3, 21100 Varese, Italy;2. The Protein Factory Research Center, Politecnico di Milano and University of Insubria, via J.H. Dunant 3, 21100 Varese, Italy |
| Abstract: | Glycopeptide antibiotics are drugs of last resort for treating severe infections caused by multi-drug resistant Gram-positive pathogens. First-generation glycopeptides (vancomycin and teicoplanin) are produced by soil-dwelling actinomycetes. Second-generation glycopeptides (dalbavancin, oritavancin, and telavancin) are semi-synthetic derivatives of the progenitor natural products. Herein, we cover past and present biotechnological approaches for searching for and producing old and new glycopeptide antibiotics. We review the strategies adopted to increase microbial production (from classical strain improvement to rational genetic engineering), and the recent progress in genome mining, chemoenzymatic derivatization, and combinatorial biosynthesis for expanding glycopeptide chemical diversity and tackling the never-ceasing evolution of antibiotic resistance. |
| Keywords: | Glycopeptide antibiotics Vancomycin Teicoplanin A40926 Dalbavancin Natural product screening Strain improvement Fermentation Genetic engineering Combinatorial biochemistry Dahp Atf acyltransferase BGC biosynthetic gene cluster CSI classical strain improvement DS desulfo DHPG dihydroxyphenylglycine DO dissolved oxygen FDA Food and Drug Administration GPA glycopeptide antibiotic ppGpp guanosine tetraphosphate HPLC high-performance liquid chromatography Gtf glycosyltransferase MRSA GlcNAc NGS next-generation sequencing MNNG Mtf methyltransferase NRPS nonribosomal peptide synthetase NMR nuclear magnetic resonance NDP nucleotide diphosphate PG peptidoglycan HPG Pdh prephenate dehydrogenase R rifampicin resistance RNAP RNA polymerase SA Stf sulfotransferase TA teicoplanin aglycone TDP thiamine diphosphate UDP uridine diphosphate VA vancomycin aglycone VPA vancomycin pseudoaglycone VH valine hydroxamate VRE vancomycin-resistant enterococci |
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