Details
| Original language | English |
|---|---|
| Article number | e202201297 |
| Journal | Chemistry - a European journal |
| Volume | 28 |
| Issue number | 54 |
| Early online date | 30 Jun 2022 |
| Publication status | Published - 27 Sept 2022 |
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.
Keywords
- antibiotics, antimicrobial resistance, natural products, oligoarylamides, photopharmacology
ASJC Scopus subject areas
- Chemical Engineering(all)
- Catalysis
- Chemistry(all)
- Organic Chemistry
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In: Chemistry - a European journal, Vol. 28, No. 54, e202201297, 27.09.2022.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
T1 - Optical Modulation of Antibiotic Resistance by Photoswitchable Cystobactamids
AU - Testolin, Giambattista
AU - Richter, Jana
AU - Ritter, Antje
AU - Prochnow, Hans
AU - Köhnke, Jesko
AU - Brönstrup, Mark
N1 - Funding Information: The study received funding from the Bundesministerium für Bildung und Forschung (BMBF, Opcybac 16GW0219K), the German Center for Infection Research (DZIF, TTU09.722), and the Helmholtz Association (VH‐GS‐202). Acknowledgments: The authorsare thankful to Ulrike Beutlingand Heike Overwinfor HRMS and LCMS measurements, Frank Surupand Christel Kakoschke for NMR measurements,and Tim Mollner for building block supply. Open Access funding enabled and organized by Projekt DEAL.
PY - 2022/9/27
Y1 - 2022/9/27
N2 - 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.
AB - 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.
KW - antibiotics
KW - antimicrobial resistance
KW - natural products
KW - oligoarylamides
KW - photopharmacology
UR - http://www.scopus.com/inward/record.url?scp=85135303175&partnerID=8YFLogxK
U2 - 10.1002/chem.202201297
DO - 10.1002/chem.202201297
M3 - Article
C2 - 35771231
AN - SCOPUS:85135303175
VL - 28
JO - Chemistry - a European journal
JF - Chemistry - a European journal
SN - 0947-6539
IS - 54
M1 - e202201297
ER -