N to the Rescue

摘要

In the war against infectious disease, bacteria are in the process of scoring a frightening tactical victory. Vancomycin is often used as the antibiotic to treat strains that have evolved resistance to other drugs, but it too is falling prey to resistant strains. A simple swap of oxygen for protonated nitrogen (more specifically, lactate for alanine) by the bacteria at vancomycin's binding site is remarkably effective at disarming the drug's mechanism of action. Xie et al. fight back by introducing a compensatory swap of their own-NH for 0 at the complementary site on the vancomycin framework. This modification leads not only to high-affinity binding with a model of the resistant target, it also conserves impressive binding affinity with a model of the native target (just a factor of 2 shy of vancomycin itself). In other words, the NH-substituted drug derivative appears to have the capacity to bind either to the lactate site or to the alanine site, which the authors rationalize by a flexible protonation equilibrium that would render the drug's nitrogen center an effective H-bond donor or acceptor.