In glycopeptide-resistant enterococci and staphylococci, high-level resistance is achieved by replacing the C-terminal D-alanyl-D-alanine of lipid II with D-alanyl-D-lactate, thus reducing glycopeptide affinity for cell wall targets. Reorganization of the cell wall in these organisms is directed by the vanHAX gene cluster. Similar self-resistance mechanisms have been reported for glycopeptide-producing actinomycetes. We investigated glycopeptide resistance in Nonomuraea sp. ATCC 39727, the producer of the glycopeptide A40926, which is the precursor of the semisynthetic antibiotic dalbavancin, which is currently in phase III clinical trials. The MIC of Nonomuraea sp. ATCC 39727 toward A40926 during vegetative growth was 4 g/ml, but this increased to ca. 20 g/ml during A40926 production. vanHAX gene clusters were not detected in Nonomuraea sp. ATCC 39727 by Southern hybridization or by PCR with degenerate primers. However, the dbv gene cluster for A40926 production contains a gene, vanY ( Actinomycetes are Gram-positive mycelial bacteria with a complex life cycle that consists of vegetative growth followed by the formation of aerial hyphae and ultimately spore formation, the last allowing both dispersal and persistence under unfavorable conditions. The onset of morphological differentiation generally coincides with the production of secondary metabolites, including many antibiotics of immense clinical and commercial importance. Antibiotic-producing actinomycetes must possess mechanisms to avoid suicide by their own toxic products. Several such resistance mechanisms have evolved, including target modification, antibiotic inactivation or sequestration, and efflux mechanisms. Microorganisms produce secondary metabolites mainly during the stationary phase of growth, and resistance genes are often coregulated with those for antibiotic production (8, 28).
In the transition to the post-petroleum economy, there is a growing demand for novel enzymes with high process performances to replace traditional chemistry with a more 'green' approach. To date, microorganisms encompass the richest source of industrial biocatalysts, but the Earth-living microbiota remains largely untapped by using traditional isolation and cultivation methods. Metagenomics, which is culture independent, represents a powerful tool for discovering novel enzymes from unculturable microorganisms. Herein, we summarize the variety of approaches adopted for mining environmental DNA and, based on a systematic literature review, we provide a comprehensive list of 332 industrially relevant enzymes discovered from metagenomes within the last three years.
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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