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Developments in Glycopeptide Antibiotics.

ABSTRACT: Glycopeptide antibiotics (GPAs) are a key weapon in the fight against drug resistant bacteria, with vancomycin still a mainstream therapy against serious Gram-positive infections more than 50 years after it was first introduced. New, more potent semisynthetic derivatives that have entered the clinic, such as dalbavancin and oritavancin, have superior pharmacokinetic and target engagement profiles that enable successful treatment of vancomycin-resistant infections. In the face of resistance development, with multidrug resistant (MDR) S. pneumoniae and methicillin-resistant Staphylococcus aureus (MRSA) together causing 20-fold more infections than all MDR Gram-negative infections combined, further improvements are desirable to ensure the Gram-positive armamentarium is adequately maintained for future generations. A range of modified glycopeptides has been generated in the past decade via total syntheses, semisynthetic modifications of natural products, or biological engineering. Several of these have undergone extensive characterization with demonstrated in vivo efficacy, good PK/PD profiles, and no reported preclinical toxicity; some may be suitable for formal preclinical development. The natural product monobactam, cephalosporin, and ?-lactam antibiotics all spawned multiple generations of commercially and clinically successful semisynthetic derivatives. Similarly, next-generation glycopeptides are now technically well positioned to advance to the clinic, if sufficient funding and market support returns to antibiotic development.

SUBMITTER: Blaskovich MAT

PROVIDER: S-EPMC5952257 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Developments in Glycopeptide Antibiotics.

Blaskovich Mark A T MAT Hansford Karl A KA Butler Mark S MS Jia ZhiGuang Z Mark Alan E AE Cooper Matthew A MA

ACS infectious diseases 20180219 5

Glycopeptide antibiotics (GPAs) are a key weapon in the fight against drug resistant bacteria, with vancomycin still a mainstream therapy against serious Gram-positive infections more than 50 years after it was first introduced. New, more potent semisynthetic derivatives that have entered the clinic, such as dalbavancin and oritavancin, have superior pharmacokinetic and target engagement profiles that enable successful treatment of vancomycin-resistant infections. In the face of resistance devel ...[more]

PMID: 29363950

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Project description:Glycopeptides are considered antibiotics of last resort for the treatment of life-threatening infections caused by relevant Gram-positive human pathogens, such as Staphylococcus aureus, Enterococcus spp. and Clostridium difficile. The emergence of glycopeptide-resistant clinical isolates, first among enterococci and then in staphylococci, has prompted research for second generation glycopeptides and a flurry of activity aimed at understanding resistance mechanisms and their evolution. Glycopeptides are glycosylated non-ribosomal peptides produced by a diverse group of soil actinomycetes. They target Gram-positive bacteria by binding to the acyl-D-alanyl-D-alanine (D-Ala-D-Ala) terminus of the growing peptidoglycan on the outer surface of the cytoplasmatic membrane. Glycopeptide-resistant organisms avoid such a fate by replacing the D-Ala-D-Ala terminus with D-alanyl-D-lactate (D-Ala-D-Lac) or D-alanyl-D-serine (D-Ala-D-Ser), thus markedly reducing antibiotic affinity for the cellular target. Resistance has manifested itself in enterococci and staphylococci largely through the expression of genes (named van) encoding proteins that reprogram cell wall biosynthesis and, thus, evade the action of the antibiotic. These resistance mechanisms were most likely co-opted from the glycopeptide producing actinomycetes, which use them to avoid suicide during antibiotic production, rather than being orchestrated by pathogen bacteria upon continued treatment. van-like gene clusters, similar to those described in enterococci, were in fact identified in many glycopeptide-producing actinomycetes, such as Actinoplanes teichomyceticus, which produces teicoplanin, and Streptomyces toyocaensis, which produces the A47934 glycopeptide. In this paper, we describe the natural and semi-synthetic glycopeptide antibiotics currently used as last resort drugs for Gram-positive infections and compare the van gene-based strategies of glycopeptide resistance among the pathogens and the producing actinomycetes. Particular attention is given to the strategy of immunity recently described in Nonomuraea sp. ATCC 39727. Nonomuraea sp. ATCC 39727 is the producer of A40926, which is the natural precursor of the second generation semi-synthetic glycopeptide dalbavancin, very recently approved for acute bacterial skin and skin structure infections. A thorough understanding of glycopeptide immunity in this producing microorganism may be particularly relevant to predict and eventually control the evolution of resistance that might arise following introduction of dalbavancin and other second generation glycopeptides into clinics.

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Developments in Glycopeptide Antibiotics.

Publications

Developments in Glycopeptide Antibiotics.

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