Old and New Glycopeptide Antibiotics: Action and Resistance

Abstract

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.

Discovery of Small‐Molecule Antibiotics against a Unique tRNA‐Mediated Regulation of Transcription in Gram‐Positive Bacteria

“…The emergence of pathogens resistant to commonly used clinical antibiotics has resulted in a surge of research for new targets and novel, “evolution proof” antibiotics . Regulators of translation and transcription are possible targets for emergent pathogens resistant to commonly used clinical antibiotics .…”

“…The emergence of pathogens resistant to commonly used clinical antibiotics has resulted in as urge of research for new targets and novel, "evolution proof" antibiotics. [52,53] Regulators of translation and transcription are possible targets for emergent pathogens resistant to commonly used clinicala ntibiotics. [9,54] Structurala nd biochemical properties of tRNA interactions with cognatea minoacyl-tRNA synthetases, the "second code", differ between bacterialp athogens and the human host.…”

Molecular mechanisms of vancomycin resistance

“…In this review, we focus on the glycopeptide resistance mechanisms which rely on the concerted action of multiple enzymes to modify peptidoglycan; these confer either high‐level (i.e., MIC >64 mg/L vancomycin) or low‐level (i.e., MIC 4 to 32 mg/L vancomycin) resistance depending on the type of modification of the terminal d ‐amino acid in Lipid II. These types of glycopeptide resistance determinants have been reviewed previously . Thus, we only briefly introduce these types and gene cassettes below to serve as a foundation for the further discussion of the structural and molecular details of individual resistance enzymes.…”

“…These types of glycopeptide resistance determinants have been reviewed previously. 5,9,[14][15][16] Thus, we only briefly introduce these types and gene cassettes below to serve as a foundation for the further discussion of the structural and molecular details of individual resistance enzymes. The replacement of D-Ala-D-Ala with D-Ala-D-lac as the terminal amino acids in Lipid II results in a 1,000-fold decrease in binding constant between vancomycin and peptidoglycan due to the loss of a single hydrogen bond, 17 thus conferring high levels of resistance (MIC >64 mg/L) ( Figure 1a).…”

Synthesis of bicyclic tripeptides inspired by the ABC-ring system of vancomycin through ruthenium-based cyclization chemistries

“…1f Within this class, multicyclic as well as side chain knotted cyclic peptides, like the conotoxins and cyclotides, 2 lantibiotics, 3 and glycopeptide antibiotics, 4 are of special interest since they combine extreme potency with shape persistent folding of the peptide backbone. The most classical and outstanding example of the effects of macrocyclization and side chain knotting is found in the heptapeptide vancomycin.…”