Optical Modulation of Antibiotic Resistance by Photoswitchable Cystobactamids

The rise of antibiotic resistance causes a serious health care problem, and its counterfeit demands novel, innovative concepts. The combination of photopharmacology, enabling a light‐controlled reversible modulation of drug activity, with antibiotic drug design has led to first photoswitchable antibiotic compounds derived from established scaffolds. In this study, we converted cystobactamids, gyrase‐inhibiting natural products with an oligoaryl scaffold and highly potent antibacterial activities, into photoswitchable agents by inserting azobenzene in the N‐terminal part and/or an acylhydrazone moiety near the C‐terminus, yielding twenty analogs that contain mono‐ as well as double‐switches. Antibiotic and gyrase inhibition properties could be modulated 3.4‐fold and 5‐fold by light, respectively. Notably, the sensitivity of photoswitchable cystobactamids towards two known resistance factors, the peptidase AlbD and the scavenger protein AlbA, was light‐dependent. While irradiation of an analog with an N‐terminal azobenzene with 365 nm light led to less degradation by AlbD, the AlbA‐mediated inactivation was induced. This provides a proof‐of‐principle that resistance towards photoswitchable antibiotics can be optically controlled.