S110: Latent antibiotics and the arylomycin class of natural products

The arylomycin class of natural product antibiotics originally elicited interest due to their novel mechanism of action, the inhibition of type I signal peptidase (SPase). However, they were dismissed as candidates for development when it was shown that they appeared to have activity against only a narrow spectrum of bacteria.  However, after reporting the first total synthesis of an arylomycin, we showed that they have potent activity against S. epidermidis, and that this pathogen evolves resistance via mutations in SPase. Interestingly, we found that the analogous mutations are naturally present in SPases of all bacteria known to be resistant, and we confirmed that they are responsible for the natural resistance of S. aureus, E. coli, and P. aeruginosa. Moreover, a diverse range of bacteria lacking SPases with these mutations are sensitive to the arylomycins, demonstrating that the spectrum of these compounds is not narrow. Although the presence of the resistance conferring mutation currently limits the therapeutic utility of these molecules, historical precedent suggests that their scaffold might be optimized to overcome this specific mechanism of resistance.  Indeed, several derivatives have been synthesized that have an increased spectrum of activity that includes S. agalactiae or S. aureus. Thus, the arylomycins would appear to be promising leads for antibiotic development. Importantly, it seems likely that most natural product antibiotics cycle through phases of broad and more narrow spectrum activity based on the competitive co-evolution of the producer and susceptible bacteria, and that many other “latent” antibiotics may exist in nature.