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

Walid A M Elgaher,Rolf W Hartmann,Katarina Cirnski,Sascha Baumann,Mostafa M Hamed,Jana Krull,Jennifer Herrmann,Lorenz Siebenbürger,Andreas Kirschning,Rolf Müller,Mark Brönstrup

doi:10.1002/chem.202000117

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.

Highlights

The ongoing prevalence of antibiotic-resistant bacteria poses an imminent threat to humanity.[1,2] the need to dis-[b] Dr S
Nature represents a rich repository of antibiotics; the major part of these natural products (NPs) have to be modified to optimize pharmacokinetic and pharmacodynamic properties.[3,4]
We used gyrase inhibition to establish the structure–activity relationship (SAR), as it is the primary target of cystobactamids in Escherichia coli.[5]

Summary

Introduction

The ongoing prevalence of antibiotic-resistant bacteria poses an imminent threat to humanity.[1,2] the need to dis-. [+] These authors contributed to this work. Cover novel antibiotics with new chemical scaffolds has been established. Nature represents a rich repository of antibiotics; the major part of these natural products (NPs) have to be modified to optimize pharmacokinetic and pharmacodynamic properties.[3,4]. (Figure 1).[5,6] Cystobactamids (1 a–1 f) have hexapeptidic structures comprised of three p-aminobenzoic acid motifs (eastern part) and two p-nitro/aminobenzoic acids (western part) connected through different linkers. The structurally simplest natural cystobactamid 507 (2), is a tripeptide representing the eastern part of most of the hexapeptides (1 a–f) (Figure 1). We report studies on the optimization of 2 because it is the only compound with appropriate physicochemical properties for oral absorption according to Lipiniski.[7]

Results and Discussion

Conclusions

Conflict of interest