Optical Modulation of Antibiotic Resistance by Photoswitchable Cystobactamids

verfasst von

Giambattista Testolin, Jana Richter, Antje Ritter, Hans Prochnow, Jesko Köhnke, Mark Brönstrup

Abstract

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.

Organisationseinheit(en)

Zentrum für Biomolekulare Wirkstoffe (BMWZ)

Externe Organisation(en)

Helmholtz-Zentrum für Infektionsforschung GmbH (HZI)
Helmholtz-Institut für Pharmazeutische Forschung Saarland (HIPS)
Universität des Saarlandes

Typ

Artikel

Journal

Chemistry - a European journal

Band

28

ISSN

0947-6539

Publikationsdatum

27.09.2022

Publikationsstatus

Veröffentlicht

Peer-reviewed

Ja

ASJC Scopus Sachgebiete

Katalyse, Organische Chemie

Elektronische Version(en)

https://doi.org/10.1002/chem.202201297 (Zugang: Offen)