Optical Modulation of Antibiotic Resistance by Photoswitchable Cystobactamids |
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Authors: | Dr Giambattista Testolin Dr Jana Richter Antje Ritter Dr Hans Prochnow Prof?Dr Jesko Köhnke Prof?Dr Mark Brönstrup |
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Institution: | 1. Department of Chemical Biology, Helmholtz Centre for Infection Research, Inhoffenstrasse 7, 38124 Braunschweig, Germany
These authors contributed equally to this work.;2. Department of Chemical Biology, Helmholtz Centre for Infection Research, Inhoffenstrasse 7, 38124 Braunschweig, Germany;3. Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Saarland University, Campus E8.1, 66123 Saarbrücken, Germany |
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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. |
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Keywords: | antibiotics antimicrobial resistance natural products oligoarylamides photopharmacology |
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