The organization of the modules necessary to biosynthesize Vancomycin is shown in Figure 1. In the biosynthesis of Vancomycin, additional modification domains are present, such as the epimerization (E) domain, which isomerizes the amino acid from one stereochemistry to another, and a thioesterase domain (TE) is used as a catalyst for cyclization and releases of the molecule via a thioesterase scission. A set of NRPS enzymes (peptide synthase VpsA, VpsB, and VpsC) are responsible for assembling the heptapeptide. (Figure 2). VpsA codes for modules 1, 2, and 3. VpsB codes for modules 4, 5, and 6, and VpsC codes for module 7. The vancomycin aglycone contains 4 D-amino acids, although the NRPSs only contain 3 epimerization domains. The origin of D-Leu at residue 1 is not known. The three peptide syntheses are located at the start of the region of the bacterial genome linked with antibiotic biosynthesis, and span 27 kb.β-hydroxytyrosine (β-HT) is synthesized prior to incorporation into the heptapeptide backbone. L-tyrosine is activated and loaded on the NRPS VpsD, hydroxylated by OxyD, and released by the thioesterase Vhp. The timing of the chlorination by halogenase VhaA during biosynthesis is currently undetermined, but is proposed to occur before the complete assembly of the heptapeptide.After the linear heptapeptide molecule is synthesized, vancomycin has to undergo further modifications, such as oxidative cross-linking and glycosylation, in trans by distinct enzymes, referred to as tailoring enzymes, to become biologically active (Figure 3). To convert the linear heptapeptide to cross-linked, glycosylated vancomycin, six enzymes, are required.
These guidelines restrict use of vancomycin to these indications:
Treatment of serious infections caused by susceptible organisms resistant to penicillins (methicillin-resistant S. aureus (MRSA) and multidrug-resistant S. epidermidis (MRSE)) or in individuals with serious allergy to penicillins
Treatment of pseudomembranous colitis caused by C. difficile; in particular, in cases of relapse or where the infection is unresponsive to metronidazole treatment (for this indication, vancomycin is given orally, rather than by its typical intravenous route)
For treatment of infections caused by Gram-positive microorganisms in patients with serious allergies to beta-lactam antimicrobials. Antibacterial prophylaxis for endocarditis following certain procedures in penicillin-hypersensitive individuals at high risk
Surgical prophylaxis for major procedures involving implantation of prostheses in institutions with a high rate of MRSA or MRSE
Early in treatment as an empiric antibiotic for possible MRSA infection while waiting for culture identification of the infecting organism
Halting the progression of primary sclerosing cholangitis and preventing symptoms; vancomycin does not cure the patient and success is limited
Treatment of endophthalmitis by intravitreal injection for gram-positive bacteria coverage. It use to prevent the condition, however, is not recommended due to the risk of side effects. Spectrum of susceptibility
Vancomycin is considered a last resort medication for the treatment of sepsis and lower respiratory tract, skin, and bone infections caused by Gram-positive bacteria.