Understanding the Genome-Wide Response of Streptomyces coelicolor to the Glycopeptide Antibiotic Teicoplanin

The glycopeptide antibiotics vancomycin and teicoplanin are clinically important as a second-line therapy to treat nosocomial infections caused by Gram-positive pathogens. Glycopeptide antibiotics universally target the terminal residues, D-Alanyl-D-Alanine on the cell wall peptidoglycan intermediate lipid II, interfering with peptidoglycan biosynthesis and weakening the cell wall. A general resistance mechanism to these antibiotics requires a core set of genes, vanRSHAX, that detect a glycopeptide (VanS) and upregulate genes (VanR) which orchestrate the remodelling of D-Ala-D-Ala on lipid II to D-Ala-D-Lactate (VanHAX), reducing glyopeptide affinity by 1000-fold. Our previous study demonstrated that altering the termini of lipid II by VanHAX action is insufficient for providing resistance to teicoplanin in S. coelicolor, which is instead mediated mainly by the elusive membrane protein, VanJ. This study further characterised VanJ by comparing the transcriptomes of a wt S. coelicolor A3(2) M600 strain and an isogenic ΔvanJ knock-out mutant after exposing cells to teicoplanin, identifying that ΔvanJ exhibited increased signs of cellular stress that were attributed to a delayed induction of genes involved in the osmotic, redox, and cell envelope stress responses. This dataset led to the functional characterisation of a group of genes with phosphatidic acid phosphatase activity which affected the sensitivity of S. coelicolor to a broad range of cell wall targeting antibiotics. One of these genes, SCO6355, significantly counteracted the intrinsic vanRSHAX resistance system of S. coelicolor, lowering its high-level vancomycin resistance (80 μg/mL) by four fold, to intermediate levels (20 μg/mL). This work demonstrates a novel mechanism which can antagonise the function of intrinsic van resistance clusters that will be important in the development of strategies that can circumvent glycopeptide resistance in clinical pathogens