The vancomycin resistance pathway in Streptomyces coelicolor primarily confers resistance to glycopeptide antibiotics, such as vancomycin and teicoplanin. These antibiotics aim to inhibit bacterial cell wall synthesis by binding to the D-Ala-D-Ala termini of peptidoglycan precursors. The resistance mechanism involves the alteration of these precursors to D-Ala-D-Lac, which reduces the binding affinity of vancomycin, rendering it ineffective. This modification is mediated by enzymes encoded by the vanHAX operon, which is activated by the VanRS two-component signal transduction system in the presence of vancomycin. The VanRS two-component regulatory system detects antibiotics and induces the operon expression thus conferring resistance to the bacteria. Additionally, novel genes such as vanJ and vanK have been identified within this system, which are essential for the full expression of vancomycin resistance and VanJ and vanK are do not exist in any previously identified vancomycin-resistant pathogen clusters. The van genes are arranged into four transcription units: vanRS, vanJ, vanK, and vanHAX and are orthologous to those seen in vancomycin-resistant enterococci. The vanS gene encodes a sensor kinase protein, which detects vancomycin and autophosphorylates VanR response regulator protein, activating it and enabling it to bind to the promoter to activate transcription. The vanH gene encodes an e D-lactate dehydrogenase, which converts pyruvate to D-lactate, a precursor for the altered peptidoglycan precursor (to counteract the effects of vancomycin, which targets the peptidoglycan by binding to D-alanine-D-alanine terminus of the peptide chains, inhibiting cell wall synthesis). A D-Ala-D-Ala dipeptidase, encoded by the vanX gene, hydrolyzes D-Ala-D-Ala dipeptides thus preventing their integration into the peptidoglycan and subsequent peptidoglycan formation in the presence of vancomycin. vanA encodes a D-alanine D-alanine ligase which synthesizes the D-Ala-D-Lac dipeptide that replaces the normal D-Ala-D-Ala in the peptidoglycan precursor, thereby reducing vancomycin's binding affinity.

Vancomycin resistance pathway (vanHAX operon) References