Journal
CHEMMEDCHEM
Volume 15, Issue 15, Pages 1429-1438Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.202000033
Keywords
antibiotics; MraY; muraymycins; nucleoside natural products; structure-activity relationships
Categories
Funding
- Australian Research Council [DE140101632]
- Griffith University
- Wellcome Trust (UK)
- University of Queensland (Australia)
- National Computational Merit Allocation Scheme - Australian Government [cj47]
- Queensland Cyber Infrastructure Foundation (QCIF) [fi49]
- Australian Research Council [DE140101632] Funding Source: Australian Research Council
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The present status of antibiotic research requires the urgent invention of novel agents that act on multidrug-resistant bacteria. The World Health Organization has classified antibiotic-resistant bacteria into critical, high and medium priority according to the urgency of need for new antibiotics. Naturally occurring uridine-derived nucleoside antibiotics have shown promising activity against numerous priority resistant organisms by inhibiting the transmembrane protein MraY (translocase I), which is yet to be explored in a clinical context. The catalytic activity of MraY is an essential process for bacterial cell viability and growth including that of priority organisms. Muraymycins are one subclass of naturally occurring MraY inhibitors. Despite having potent antibiotic properties, the structural complexity of muraymycins advocates for simplified analogues as potential lead structures. Herein, we report a systematic structure-activity relationship (SAR) study of serine template-linked, simplified muraymycin-type analogues. This preliminary SAR lead study of serine template analogues successfully revealed that the complex structure of naturally occurring muraymycins could be easily simplified to afford bioactive scaffolds against resistant priority organisms. This study will pave the way for the development of novel antibacterial lead compounds based on a simplified serine template.
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