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Cystobactamid 507: Concise Synthesis, Mode of Action, and Optimization toward More Potent Antibiotics
Author(s) -
Elgaher Walid A. M.,
Hamed Mostafa M.,
Baumann Sascha,
Herrmann Jennifer,
Siebenbürger Lorenz,
Krull Jana,
Cirnski Katarina,
Kirschning Andreas,
Brönstrup Mark,
Müller Rolf,
Hartmann Rolf W.
Publication year - 2020
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.202000117
Subject(s) - antibiotics , mode of action , intercalation (chemistry) , combinatorial chemistry , antimicrobial , antibacterial activity , topoisomerase , chemistry , bacteria , stereochemistry , computational biology , broad spectrum , dna , microbiology and biotechnology , biology , biochemistry , genetics , organic chemistry
Lack of new antibiotics and increasing antimicrobial resistance are among the main concerns of healthcare communities nowadays, and these concerns necessitate the search for novel antibacterial agents. Recently, we discovered the cystobactamids—a novel natural class of antibiotics with broad‐spectrum antibacterial activity. In this work, we describe 1) a concise total synthesis of cystobactamid 507, 2) the identification of the bioactive conformation using noncovalently bonded rigid analogues, and 3) the first structure–activity relationship (SAR) study for cystobactamid 507 leading to new analogues with high metabolic stability, superior topoisomerase IIA inhibition, antibacterial activity and, importantly, stability toward the resistant factor AlbD. Deeper insight into the mode of action revealed that the cystobactamids employ DNA minor‐groove binding as part of the drug–target interaction without showing significant intercalation. By designing a new analogue of cystobactamid 919‐2, we finally demonstrated that these findings could be further exploited to obtain more potent hexapeptides against Gram‐negative bacteria.