Glycopeptide antibiotics: Back to the future

Abstract

Glycopeptide antibiotics have been a key weapon in the fight against bacterial infections for over half a century, with the progenitors, vancomycin (1) and teicoplanin (2), still used extensively. The increased occurrence of resistance and the effectiveness of these 'last resort' treatments for Gram-positive infections has led to the discovery and clinical development of second generation, semisynthetic lipoglycopeptide derivatives such as telavancin (3), dalbavancin (4) and oritavancin (5), which all possess broader spectra of activity and improved pharmacokinetic properties. Two of these new antibiotics, telavancin (3) and dalbavancin (4), were approved in the past 5 years and the third, oritavancin (5), is awaiting regulatory approval. In this review, the discovery, development and associated resistance of vancomycin (1) and teicoplanin (2), and semi-synthetic glycopeptides, telavancin (3), dalbavancin (4) and oritavancin (5), are detailed. The clinical implications of glycopeptide resistance, especially vancomycin (1), as well as the future prospects for current glycopeptide drugs and the development of new glycopeptides are discussed.

Taxonomy, Physiology, and Natural Products of Actinobacteria

“…For example, streptothricin is found in some 10% of all streptomycetes isolated randomly from soil and streptomycin is found in 1% and actinomycin in 0.1%, while conversely, erythromycin and vancomycin are found in around 10 Ϫ5 soil isolates, and daptomycin is found only at a frequency of around 10 Ϫ7 (412). Major classes of clinical antibiotics produced by actinomycetes are the following: aminoglycosides (neomycin, kanamycin, streptomycin (413)(414)(415), angucyclines (auricin; also, antitumor agents like landomycin and moromycin (416), ansamycins (rifamycin, geldanamycin) (417), anthracyclines (primarily antitumor agents, e.g., daunorubicin) (418,419), ␤-lactams (cephamycins) (420) and also the important ␤-lactamase inhibitor clavulanic acid (421,422), chloramphenicol (423), glutarimides (cycloheximide) (424), glycopeptides (vancomycin, teichoplanin) (425,426), lipopeptides (daptomycin) (427), lantibiotics (mersacidin, actagardine) (272), macrolides (clarythromycin, erythromycin, tylosin, clarithromycin) (428,429), oxazolidinones (cycloserine) (430), streptogramins (streptogramin) (431), and tetracyclines (432). The producing capacity of individual actinomycetes can also vary enormously.…”

Antibiotics in the clinical pipeline at the end of 2015

“…Antibiotics and β-lactamase inhibitor combinations launched from 2000 to 2015, their antibiotic class, activity spectra, country of first approval, lead source and NP lead source if applicable Xydalba, BI-397) is one of two new glycopeptides that received FDA approval in 2014 after decades of development [51][52][53]. It is a semi-synthetic lipopeptide analog of the teicoplanin-like glycopeptide A40926 Factor B, modified by amidation of the C-terminal acid group with N,N-dimethyl-1,3-diaminopropane.Originally developed at the Lepitit Research Centre of Marion Merrell Dow, it passed through the hands of Hoechst, Biosearch Italia S.p.A, Vicuron Pharmaceuticals, Pfizer (Groton, CT, USA), and finally Durata Therapeutics, who acquired the program in 2009.…”

In vivo efficacy and pharmacological properties of a novel glycopeptide (YV4465) against vancomycin-intermediate Staphylococcus aureus

“…Semisynthetic lipoglycopeptides (oritavancin, dalbavancin and telavancin) were shown to exhibit high antibacterial activity against resistant strains with an improved pharmacological profile [6,8]. Recently, the US Food and Drug Administration (FDA) approved all of these semisynthetic glycopeptides for the treatment of skin infections caused by MRSA [6,8]. Other clinically approved antibiotics to treat serious Gram-positive bacterial infections are linezolid, ceftaroline, quinupristin/dalfopristin and daptomycin [9,10].…”

“…Significant approaches have been implemented for the development of next-generation glycopeptide antibiotics that address the widespread prevalence of vancomycin resistance [5][6][7]. Semisynthetic lipoglycopeptides (oritavancin, dalbavancin and telavancin) were shown to exhibit high antibacterial activity against resistant strains with an improved pharmacological profile [6,8]. Recently, the US Food and Drug Administration (FDA) approved all of these semisynthetic glycopeptides for the treatment of skin infections caused by MRSA [6,8].…”