Probes track vancomycin-induced cell wall changes

The antibiotic vancomycin works by interfering with bacterial cell wall synthesis. Some bacteria evade this drug by altering their cell wall precursors so they’re insensitive to it. These adaptations affect the substrates of key enzymes—a dipeptidase that degrades drug-sensitive building blocks and a ligase that stitches together drug-resistant ones. Marcos M. Pires and Sean E. Pidgeon of Lehigh University have now developed a pair of probes for monitoring in live bacteria the changes that lead to vancomycin resistance. Both probes include alkyne handles for attaching fluorescent labels via click chemistry. One probe is a synthetic dipeptide analog of the dipeptidase substrate (Angew. Chem. Int. Ed. 2017, DOI: 10.1002/anie.201704851). Decreasing fluorescence levels of that probe are associated with development of drug resistance. The other probe is an alkyne-containing analog of the d-lactate that is a substrate of the ligase (ACS Chem. Biol. 2017, DOI: 10.1021/acschembio.7b00412). That probe signals development of drug resistance via increasing fluorescence levels. The researchers used the probes to monitor changes in the cell wall composition associated with drug resistance in response to increasing vancomycin concentrations. In addition, the researchers distinguished between subtypes of vancomycin-resistant bacteria.