Dataset Information

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.

SUBMITTER: Elgaher WAM

PROVIDER: S-EPMC7317206 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Elgaher Walid A M WAM Hamed Mostafa M MM Baumann Sascha S Herrmann Jennifer J Siebenbürger Lorenz L Krull Jana J Cirnski Katarina K Kirschning Andreas A Brönstrup Mark M Müller Rolf R Hartmann Rolf W RW

Chemistry (Weinheim an der Bergstrasse, Germany) 20200428 32

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, a ...[more]

PMID: 31984562

Similar Datasets

Project description:UnlabelledDengue viruses (DV) represent a significant global health burden, with up to 400 million infections every year and around 500,000 infected individuals developing life-threatening disease. In spite of attempts to develop vaccine candidates and antiviral drugs, there is a lack of approved therapeutics for the treatment of DV infection. We have previously reported the identification of ST-148, a small-molecule inhibitor exhibiting broad and potent antiviral activity against DV in vitro and in vivo (C. M. Byrd et al., Antimicrob. Agents Chemother. 57:15-25, 2013, doi:10 .1128/AAC.01429-12). In the present study, we investigated the mode of action of this promising compound by using a combination of biochemical, virological, and imaging-based techniques. We confirmed that ST-148 targets the capsid protein and obtained evidence of bimodal antiviral activity affecting both assembly/release and entry of infectious DV particles. Importantly, by using a robust bioluminescence resonance energy transfer-based assay, we observed an ST-148-dependent increase of capsid self-interaction. These results were corroborated by molecular modeling studies that also revealed a plausible model for compound binding to capsid protein and inhibition by a distinct resistance mutation. These results suggest that ST-148-enhanced capsid protein self-interaction perturbs assembly and disassembly of DV nucleocapsids, probably by inducing structural rigidity. Thus, as previously reported for other enveloped viruses, stabilization of capsid protein structure is an attractive therapeutic concept that also is applicable to flaviviruses.ImportanceDengue viruses are arthropod-borne viruses representing a significant global health burden. They infect up to 400 million people and are endemic to subtropical and tropical areas of the world. Currently, there are neither vaccines nor approved therapeutics for the prophylaxis or treatment of DV infections, respectively. This study reports the characterization of the mode of action of ST-148, a small-molecule capsid inhibitor with potent antiviral activity against all DV serotypes. Our results demonstrate that ST-148 stabilizes capsid protein self-interaction, thereby likely perturbing assembly and disassembly of viral nucleocapsids by inducing structural rigidity. This, in turn, might interfere with the release of viral RNA from incoming nucleocapsids (uncoating) as well as assembly of progeny virus particles. As previously reported for other enveloped viruses, we propose the capsid as a novel tractable target for flavivirus inhibitors.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets