Synthesis of visible light photoswitchable antibiotics as a tool to combat resistance

Abstract

The appearance and rise of antibiotic resistance is a public health concern that will lead to increasing pressure on the world’s healthcare systems. Previously treatable infections are set to become one of the major causes of mortality worldwide due to the development of resistance. New drugs as well as new strategies are needed to combat this situation; in this context, modulation of antibiotic activity is a useful tool to prevent the rise of further resistance. Photopharmacology allows spatiotemporal control of antibiotic activity through light and is an attractive area of research in the development of new antibiotic strategies. Photocontrolled antibiotics could be released into the environment inactivated after acting on the body, removing evolutionary pressure on microorganisms and decreasing the rise of resistance. One such photoswitchable class of molecules are azobenzenes. Most azobenzenes isomerize under UV light, hostile to life, and while reports of harmless, red-shifted tetra-ortho-methoxy-azobenzenes exist since 2011, their use was limited due to low yields and harsh reaction conditions used to prepare them. More efficient and versatile synthetic pathways to prepare tetra-ortho-methoxy-azobenzenes were developed recently. This opened up new synthetic and application possibilities for this family of compounds, such as their use in solid phase peptide synthesis as amino-acid analogues. A library of photoswitchable analogues of the antibiotic peptide Tyrocidine A that incorporate a tetra-ortho-methoxy-azobenzene amino-acid was prepared and purified, verifying its compatibility with conventional SPPS methods. In the future, it could be used to test and study isomerization under red light and in vitro biological activity. Key concepts: photopharmacology, azobenzenes, solid phase peptide synthesis