Details
| Original language | English |
|---|---|
| Pages (from-to) | 1316-1334 |
| Number of pages | 19 |
| Journal | Chemical science |
| Volume | 11 |
| Issue number | 5 |
| Early online date | 10 Dec 2019 |
| Publication status | Published - 7 Feb 2020 |
Abstract
There is an alarming scarcity of novel chemical matter with bioactivity against multidrug-resistant Gram-negative bacterial pathogens. Cystobactamids, recently discovered natural products from myxobacteria, are an exception to this trend. Their unusual chemical structure, composed of oligomeric para-aminobenzoic acid moieties, is associated with a high antibiotic activity through the inhibition of gyrase. In this study, structural determinants of cystobactamid's antibacterial potency were defined at five positions, which were varied using three different synthetic routes to the cystobactamid scaffold. The potency against Acinetobacter baumannii could be increased ten-fold to an MIC (minimum inhibitory concentration) of 0.06 μg mL-1, and the previously identified spectrum gap of Klebsiella pneumoniae could be closed compared to the natural products (MIC of 0.5 μg mL-1). Proteolytic degradation of cystobactamids by the resistance factor AlbD was prevented by an amide-triazole replacement. Conjugation of cystobactamid's N-terminal tetrapeptide to a Bodipy moiety induced the selective localization of the fluorophore for bacterial imaging purposes. Finally, a first in vivo proof of concept was obtained in an E. coli infection mouse model, where derivative 22 led to the reduction of bacterial loads (cfu, colony-forming units) in muscle, lung and kidneys by five orders of magnitude compared to vehicle-treated mice. These findings qualify cystobactamids as highly promising lead structures against infections caused by Gram-positive and Gram-negative bacterial pathogens.
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In: Chemical science, Vol. 11, No. 5, 07.02.2020, p. 1316-1334.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
T1 - Synthetic studies of cystobactamids as antibiotics and bacterial imaging carriers lead to compounds with high in vivo efficacy
AU - Testolin, Giambattista
AU - Cirnski, Katarina
AU - Rox, Katharina
AU - Prochnow, Hans
AU - Fetz, Verena
AU - Grandclaudon, Charlotte
AU - Mollner, Tim
AU - Baiyoumy, Alain
AU - Ritter, Antje
AU - Leitner, Christian
AU - Krull, Jana
AU - Van Den Heuvel, Joop
AU - Vassort, Aurelie
AU - Sordello, Sylvie
AU - Hamed, Mostafa M.
AU - Elgaher, Walid A.M.
AU - Herrmann, Jennifer
AU - Hartmann, Rolf W.
AU - Müller, Rolf
AU - Brönstrup, Mark
N1 - Funding Information: The study was funded by an internal Pre4D grant of the HZI and by a scholarship of the HZI graduate school for G. Testolin. The studies were co-funded by the German Centre for Infection Research (DZIF; Grant no TTU09.710) and the BMBF Project “Wirkstoffentwicklung auf Basis von Naturstoffen zur Bekämpfung von Infektionskrankheiten” (no GGNATM27).
PY - 2020/2/7
Y1 - 2020/2/7
N2 - There is an alarming scarcity of novel chemical matter with bioactivity against multidrug-resistant Gram-negative bacterial pathogens. Cystobactamids, recently discovered natural products from myxobacteria, are an exception to this trend. Their unusual chemical structure, composed of oligomeric para-aminobenzoic acid moieties, is associated with a high antibiotic activity through the inhibition of gyrase. In this study, structural determinants of cystobactamid's antibacterial potency were defined at five positions, which were varied using three different synthetic routes to the cystobactamid scaffold. The potency against Acinetobacter baumannii could be increased ten-fold to an MIC (minimum inhibitory concentration) of 0.06 μg mL-1, and the previously identified spectrum gap of Klebsiella pneumoniae could be closed compared to the natural products (MIC of 0.5 μg mL-1). Proteolytic degradation of cystobactamids by the resistance factor AlbD was prevented by an amide-triazole replacement. Conjugation of cystobactamid's N-terminal tetrapeptide to a Bodipy moiety induced the selective localization of the fluorophore for bacterial imaging purposes. Finally, a first in vivo proof of concept was obtained in an E. coli infection mouse model, where derivative 22 led to the reduction of bacterial loads (cfu, colony-forming units) in muscle, lung and kidneys by five orders of magnitude compared to vehicle-treated mice. These findings qualify cystobactamids as highly promising lead structures against infections caused by Gram-positive and Gram-negative bacterial pathogens.
AB - There is an alarming scarcity of novel chemical matter with bioactivity against multidrug-resistant Gram-negative bacterial pathogens. Cystobactamids, recently discovered natural products from myxobacteria, are an exception to this trend. Their unusual chemical structure, composed of oligomeric para-aminobenzoic acid moieties, is associated with a high antibiotic activity through the inhibition of gyrase. In this study, structural determinants of cystobactamid's antibacterial potency were defined at five positions, which were varied using three different synthetic routes to the cystobactamid scaffold. The potency against Acinetobacter baumannii could be increased ten-fold to an MIC (minimum inhibitory concentration) of 0.06 μg mL-1, and the previously identified spectrum gap of Klebsiella pneumoniae could be closed compared to the natural products (MIC of 0.5 μg mL-1). Proteolytic degradation of cystobactamids by the resistance factor AlbD was prevented by an amide-triazole replacement. Conjugation of cystobactamid's N-terminal tetrapeptide to a Bodipy moiety induced the selective localization of the fluorophore for bacterial imaging purposes. Finally, a first in vivo proof of concept was obtained in an E. coli infection mouse model, where derivative 22 led to the reduction of bacterial loads (cfu, colony-forming units) in muscle, lung and kidneys by five orders of magnitude compared to vehicle-treated mice. These findings qualify cystobactamids as highly promising lead structures against infections caused by Gram-positive and Gram-negative bacterial pathogens.
UR - http://www.scopus.com/inward/record.url?scp=85079237979&partnerID=8YFLogxK
U2 - 10.1039/c9sc04769g
DO - 10.1039/c9sc04769g
M3 - Article
AN - SCOPUS:85079237979
VL - 11
SP - 1316
EP - 1334
JO - Chemical science
JF - Chemical science
SN - 2041-6520
IS - 5
ER -