Newest perspectives of glycopeptide antibiotics: biosynthetic cascades, novel derivatives, and new appealing antimicrobial applications

Abstract

Glycopeptide antibiotics (GPAs) are a family of non-ribosomal peptide natural products with polypeptide skeleton characteristics, which are considered the last resort for treating severe infections caused by multidrug-resistant Gram-positive pathogens. Over the past few years, an increasing prevalence of Gram-positive resistant strain “superbugs” has emerged. Therefore, more efforts are needed to study and modify the GPAs to overcome the challenge of superbugs. In this mini-review, we provide an overview of the complex biosynthetic gene clusters (BGCs), the ingenious crosslinking and tailoring modifications, the new GPA derivatives, the discoveries of new natural GPAs, and the new applications of GPAs in antivirus and anti-Gram-negative bacteria. With the development and interdisciplinary integration of synthetic biology, next-generation sequencing (NGS), and artificial intelligence (AI), more GPAs with new chemical structures and action mechanisms will constantly be emerging. Graphical abstract

Metabolomic analysis in Amycolatopsis keratiniphila disrupted the competing ECO0501 pathway for enhancing the accumulation of vancomycin

“…The sugar donors in the biosynthesis of vancomycin are glucose and non-conventional sugar vancosamine (Xu et al 1014;Tian et al 2023;Thibodeaux et al 2008). Vancosamine, whose biosynthesis has been studied, is derived from glucose-1-phosphate via the glycolytic intermediate glucose-6-phosphate (Xu et al 2014;Joshua 2019;Milke and Marienhagen 2020).…”

Navigating Antibacterial Frontiers: A Panoramic Exploration of Antibacterial Landscapes, Resistance Mechanisms, and Emerging Therapeutic Strategies

“…Glycopeptides are glycosylated nonribosomal peptides that are composed of a tricyclic or tetracyclic polypeptide scaffold and typically a heptapeptide scaffold made by proteogenic and nonproteogenic amino acids alongside sugar residues, chlorine atoms, methyl groups, or lipid chains. , They display antibacterial activity against Gram-positive bacteria typically by inhibiting cell wall biosynthesis due to binding to the C-terminal d -Ala- d -Ala moiety of the peptidoglycan precursor lipid II, which prevents transglycosylation and transpeptidation for cell wall synthesis. − They are effective against S. aureus (including MRSA), Enterococcus spp., C . difficile , and healthcare-associated infections that are resistant to other antibiotics like E. faecalis and E. faecium .…”

“…Some members of approved drugs of this group are vancomycin (1958), teicoplanin (1988), telavancin (2009), dalbavancin (2014), and oritavancin (2014) . Many novel derivatives and new glycopeptides are also being developed, studied, and optimized. − , Known resistance mechanisms include target site modification, cell wall thickening, enzymatic modification of vancomycin, and efflux pumps …”

“…279 Many novel derivatives and new glycopeptides are also being developed, studied, and optimized. [269][270][271]280 Known resistance mechanisms include target site modification, cell wall thickening, enzymatic modification of vancomycin, and efflux pumps. 281 Lipopeptides and Lipoglycopeptides.…”

Cross-Talking of Pathway-Specific Regulators in Glycopeptide Antibiotics (Teicoplanin and A40926) Production

“…The latter natural precursor of dalbavancin—A40926—is biosynthesized by the uncommon actinobacterium Nonomuraea gerenzanensis ATCC 39727 [ 20 ]. The renewed interest for these antibiotics and their newest developments, highlighting the importance of developing next-generation semisynthetic GPAs with enhanced antibacterial activities and improved safety profiles, have been recently stated in different reviews [ 21 , 22 , 23 , 24 , 25 ]. Recent efforts have also aimed at developing targeted therapies, and advances have been made in extending the activity of GPAs toward Gram-negative organisms [ 21 , 22 , 23 , 24 , 25 ].…”