Cystobactamid 507: Concise Synthesis, Mode of Action, and Optimization toward More Potent Antibiotics

Abstract

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.

In vivo and in vitro reconstitution of unique key steps in cystobactamid antibiotic biosynthesis

“…Most of the cystobactamids with other linker moieties are inactive or show only weak antibacterial activity. Furthermore, total syntheses for several native cystobactamids and synthetic derivatives with improved antibacterial activity or metabolic stability were described 2 , 4 – 7 . Notably, cystobactamids show structural similarity with albicidins (shown in Fig.…”

Natural and Synthetic Oligoarylamides: Privileged Structures for Medical Applications

“…Structural data on the exact binding site of cystobactamids or albicidin, respectively, to gyrase or to DNA or to the gyrase‐DNA complex during passage of the DNA strand through the N‐gate are not yet available [104] . Initial investigations suggest that the oligobenzamidic part of the cystobactamids (rings C–E) could bind to the minor groove of the dsDNA [10e] . Therefore, the mode of action of these antibiotics could not yet be elucidated in full detail.…”

Metagenome‐Guided Analogue Synthesis Yields Improved Gram‐Negative‐Active Albicidin‐ and Cystobactamid‐Type Antibiotics

“…A convergent synthesis was therefore envisioned that would enable facile access to all six structures from a minimum number of monomer building blocks. In keeping with previous synthetic routes, [15] each congener was disconnected retrosynthetically into three fragments: the N-terminal dipeptide, the central MO-Asn or CN-Ala unit, and the C-terminal tripeptide. Figure 3 b shows a representative retrosynthetic analysis of both a predicted albicidin and cystobactamid congener.…”