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 -