Optical Modulation of Antibiotic Resistance by Photoswitchable Cystobactamids

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, gyraseinhibiting 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 AlbAmediated inactivation was induced. This provides a proof-ofprinciple that resistance towards photoswitchable antibiotics can be optically controlled.

Smart Wearable Patches Using Light‐Controlled Activation and Delivery of Photoswitchable Antimicrobial Peptides

“…Notably, cis ‐to‐ trans deactivation was shown to be rapid, with the maximum trans ‐enriched PSS achieved within 30 seconds of irradiation with visible light (405 nm) (see Figure S8). This rapid deactivation of 5 b potentially confines the active peptide ( cis ‐enriched PSS) to the infected site, thus limiting off‐target effects on commensal microbiota and minimizing antimicrobial resistance [15] . The ratio of trans to cis isomers in each enriched photostationary state of peptide 5 b was calculated through integration of selected signals from the corresponding 1 H NMR spectrum.…”

Exploring antibiotic resistance with chemical tools

“…46 More recently, (spatio)temporally activated antibiotics have gathered attention and can be used for temporarily activating antibiotics 23,47 to dissect their mechanism of action and how bacteria develop resistance against them. 48 Here, I will discuss these three different types of modifications and highlight several of their successful applications. For a comprehensive overview I refer the reader to recent reviews on the individual topics.…”

“…More recently, (spatio)temporally activated antibiotics have gathered attention and can be used for temporarily activating antibiotics 23,47 to dissect their mechanism of action and how bacteria develop resistance against them. 48…”

Transcription activation by the resistance protein AlbA as a tool to evaluate derivatives of the antibiotic albicidin

“…The broad activity spectrum and its unique gyrase binding mode make albicidin an attractive lead for pharmaceutical development, despite several known (auto-)resistance mechanisms, 8,22–25 which may be overcome by targeted engineering of the compound. 16,19,26…”

“…The broad activity spectrum and its unique gyrase binding mode make albicidin an attractive lead for pharmaceutical development, despite several known (auto-)resistance mechanisms, 8,[22][23][24][25] which may be overcome by targeted engineering of the compound. 16,19,26 The resistance factor AlbA is a member of the MerR-like transcription regulator family, which typically reshape promoter DNA to induce transcription of downstream genes. 27 Many MerR-family transcription factors act as sensors of unfavourable conditions, such as metal-or oxidative stressresponse sensors and multi-drug responsive regulators, by employing a ligand-binding domain (LBD).…”