Cystobactamid 507: Concise Synthesis, Mode of Action, and Optimization toward More Potent Antibiotics
Open Access
- 5 June 2020
- journal article
- research article
- Published by Wiley in Chemistry – A European Journal
- Vol. 26 (32), 7219-7225
- https://doi.org/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.This publication has 30 references indexed in Scilit:
- Entdeckung und Totalsynthese von natürlichen Cystobactamid‐Derivaten mit herausragender Aktivität gegen Gram‐negative PathogeneAngewandte Chemie, 2017
- Discovery and Total Synthesis of Natural Cystobactamid Derivatives with Superior Activity against Gram‐Negative PathogensAngewandte Chemie, 2017
- Natural Products as Sources of New Drugs from 1981 to 2014Journal of Natural Products, 2016
- Antibacterial drug discovery in the resistance eraNature, 2016
- Cystobactamids: Myxobacterial Topoisomerase Inhibitors Exhibiting Potent Antibacterial ActivityAngewandte Chemie, 2014
- Cystobactamide: Topoisomerase-Inhibitoren aus Myxobakterien mit hoher antibakterieller AktivitätAngewandte Chemie, 2014
- Antibiotic-Resistant Bugs in the 21st Century — A Clinical Super-ChallengeThe New England Journal of Medicine, 2009
- Antibacterial Natural Products in Medicinal Chemistry—Exodus or Revival?Angewandte Chemie-International Edition, 2006
- Antibakterielle Naturstoffe in der medizinischen Chemie – Exodus oder Renaissance?Angewandte Chemie, 2006
- Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settingsAdvanced Drug Delivery Reviews, 2001