Vancomycin was introduced in 1958 as an antibiotic that was effective against penicillin- and methicillin-resistant strains of Gram-positive bacteria. However, it wasn't widely used until methicillin-resistant strains became more prevalent in the 1980s.
Development of Resistance
Development of resistance is associated with overuse of antibiotics. Antibiotic resistant strains are routinely identified shortly after the introduction of any new antibiotic, so it is no surprise to note that vancomycin tolerant strains began to be reported shortly after this drug began to be used more frequently. The first case of a vancomycin-resistant bacterial strain - Enterococcus faecium - was reported in 1988, and since then, the prevalence of vancomycin-resistant enterococci has increased dramatically, according to Dr Patrice Courvalin (Courvalin, Clin Infect Dis, 2006).
The first report of Staphylococcus aureus, the same species of bacteria as MRSA, with reduced susceptibility to vancomycin was identified in 1996 and reported by Hiramatsu et al in the Journal of Antimicrobial Chemotherapy (Hiramatsu et al, 1997). However, a fully resistant strain was not isolated until 2002, (Chang et al, New Eng J Med, 2003). Fully resistant S. aureus strains are still rare, but the incidence of strains with some degree of tolerance to vancomycin is rising rapidly and becoming a considerable problem.
Mechanism of Action of Vancomycin
Vancomycin is bacteriostatic, which means it doesn't actually kill the bacteria. Instead, it stops them from growing and dividing, relying on the immune system to finish the job. It works by physically blocking the formation of new cell walls during the bacterial growth and division phases.
Vancomycin binds to a specific part of certain cell wall proteins in Gram-positive bacteria called peptidoglycans. Gram-negative bacteria do not have these proteins, and so are not affected by vancomycin. The drug enters the cell and binds to these peptidoglycans before they have become part of the cell wall, and this prevents them from being incorporated (Courvalin, 2006). Thus, vancomycin halts the formation of new cell walls when bacteria divide and grow. This effectively prevents bacteria from dividing, therefore stops the infecting bacterial colony from becoming any larger.
Mechanisms of Bacterial Resistance to Vancomycin
Bacterial resistance to vancomycin focuses on combating the role of the drug in inhibiting cell wall formation. Six acquired resistance genes have been identified in enterococci, although only two, VanA and VanB, are widely prevalent (Werner et al, Eurosurveillance, 2008), and only VanA has been detected in S. aureus (Courvalin, 2006). These genes are thought to play various roles in overcoming the effect of vancomycin on cell wall formation.
Resistance through the VanA gene is mediated by changes made to the peptidoglycan binding site, significantly reducing the strength of vancomycin binding. The VanA gene induces the expression of an enzyme that causes an amino acid – lactate – to be added to the end of the peptidoglycan protein chain. This extra amino acid blocks accessibility to the binding site and reduces the action of the antibiotic (Courvalin, 2006).
The VanB, VanC, VanD, VanE and VanG genes function in a similar way to Van A, but with differences in how they are regulated, in what changes to the binding site are made, and whether or not they confer resistance to teicoplanin, another antibiotic that is related to vancomycin (Courvalin, 2006).
Cell wall thickening is a feature of less susceptible, or intermediate, strains of S. aureus. Other proteins in the cell wall can serve as false targets, which bind to vancomycin instead of the original targets - the peptidoglycans. Moreover, the presence of these decoy proteins in the cell wall also means that the drug is trapped before it reaches the inside of the cell, therefore less antibiotic reaches the cell wall from reaching its real peptidoglycan targets (Cui et al, Antimicrob Agents Chemother, 2006).
As more antibiotics are developed and used, bacteria are likely to quickly develop resistance mechanisms against them, indeed cases of resistance to newer antibiotics, including those active against MRSA, have been reported. Focused research and development of new antimicrobial agents is therefore both urgent and necessary.
References
Hiramatsu K et al. J Antimicrob Chemother 1997; 40:135-136 (letter)
Chang S et al. New Eng J Med 2003; 348:1342-1347.
Courvalin P. Clin Infect Dis 2006; 42(Suppl 1):S25-S34.
Cui L et al. Antimicrob Agents Chemother 2006; 50(2):428-438.
Werner G et al. Eurosurveillance 2008; 13(47):1-11.
Lindsay Napier - I started my scientific career with a BSc in Biological sciences, then continued into the laboratory, studying for a PhD by researching ...
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