Antibiotic Diversity Can Be Controlled On Multiple Levels

Chemists in England have demonstrated the ability to harness multiple levels of molecular control to selectively produce specific members of the pacidamycin family of antibiotics and to create additional analogs (Chem. Sci., DOI: 10.1039/c1sc00378j). Pacidamycins are a suite of some 20 uridyl peptides produced by the bacterium Streptomyces coeruleorubidus. They differ by having alternate amino acids at each end of the molecule. Scientists typically assume that this type of molecular diversity is the result of enzyme promiscuity with different substrates that is governed by a core set of genes. Rebecca J. M. Goss, Sabine Grüschow, and Emma J. Rackham of the University of East Anglia discovered that is true for pacidamycins, but that the selection for the terminal amino acid substituents is also guided by two genes located away from the core set. One of those genes controls production of m-tyrosine, whereas the other in combination with one of the core genes determines whether m-tyrosine or alanine ends up on one end of the molecule. By engineering a different bacterium, Streptomyces lividans, with the core set of genes plus the two outlying genes, the researchers created a multilevel control system that allows them to make any single pacidamycin they wish at a time in a “dial-a-molecule” fashion.