One interesting thing about the mechanism of Vancomycin is that it doesn't target a protein, it targets a precursor of the cell wall. So a resistance mechanism

One interesting thing about the mechanism of Vancomycin is that it doesn't target a protein, it targets a precursor of the cell wall. So a resistance mechanism can't just change the target protein, it has to change the biosynthetic pathway to use a different precursor for the cell wall. And this is how resistance against Vancomycin works, the bacteria start using D-Ala-D-Lac instead of D-Ala-D-Ala, and Vancomycin binds a 1000 times less tightly to that. One of the changes in this new Vancomycin derivative makes it bind better to D-Ala-D-Lac, neutralizing this particular mechanism for resistance.