Muraymycin-type nucleoside antibiotics: studies on target interaction and on bacterial cellular uptake

• Applicant: Professor Dr. Christian Ducho
• Subject Area: Pharmacy ; Biological and Biomimetic Chemistry
• Term: from 2016 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 327577170

Due to emerging pathogenic bacteria with resistances against established antimicrobial agents, the development of novel antibiotics is urgently needed. Ideally, such novel antimicrobial compounds should display new or yet unexploited modes of action. Nucleoside antibiotics, which also include muraymycins, are natural products inhibiting the bacterial membrane protein MraY. MraY is a key enzyme in the intracellular part of peptidoglycan biosynthesis and therefore essential for the assembly of the bacterial cell wall.There are several routes for the chemical total synthesis of muraymycin analogues as well as some data on structure-activity relationships available. Nevertheless, many molecular details of the interaction of muraymycins and their analogues with MraY are not elucidated yet. Based on a recently reported X-ray crystal structure of MraY with a muraymycin ligand, it is envisioned to synthesise novel analogues and to study their biological properties. These compounds will furnish further insights into the ligand-target interaction and might also display increased biological potency. These investigations will be complemented by studies on the bacterial cellular uptake of the intracellularly acting muraymycin analogues.Overall, this research project will fundamentally contribute to the molecular understanding of the antibiotic action of muraymycins and their analogues. The obtained results will enable the design of synthetically readily accessible simplified muraymycin analogues combining strong inhibitory potency towards MraY with sufficent cellular uptake, thus representing potential candidate compounds for antimicrobial drug development.

• DFG Programme: Research Grants