Simplified Novel Muraymycin Analogues; using a Serine Template Strategy for Linking Key Pharmacophores

Bhautikkumar Patel; Rachel V Kerr; Alpeshkumar K Malde; Matthew Zunk; Timothy D H Bugg; Gary Grant; Santosh Rudrawar

doi:10.1002/cmdc.202000033

Simplified Novel Muraymycin Analogues; using a Serine Template Strategy for Linking Key Pharmacophores

ChemMedChem. 2020 Aug 5;15(15):1429-1438. doi: 10.1002/cmdc.202000033. Epub 2020 Jun 12.

Authors

Bhautikkumar Patel^{1

2

3}, Rachel V Kerr⁴, Alpeshkumar K Malde^{5

6}, Matthew Zunk^{1

2

3}, Timothy D H Bugg⁴, Gary Grant^{1

2

3}, Santosh Rudrawar^{1

2

3}

Affiliations

¹ Menzies Health Institute Queensland, Griffith University, Gold Coast, QLD 4222, Australia.
² School of Pharmacy and Pharmacology, Griffith University, Gold Coast, QLD 4222, Australia.
³ Quality Use of Medicines Network, Griffith University, Gold Coast, QLD 4222, Australia.
⁴ Department of Chemistry, University of Warwick, Coventry, CV4 7AL, UK.
⁵ Institute for Glycomics, Griffith University, Gold Coast, QLD 4222, Australia.
⁶ MaldE Scientific, Australia.

PMID: 32476294
DOI: 10.1002/cmdc.202000033

Abstract

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.

Keywords: MraY; antibiotics; muraymycins; nucleoside natural products; structure-activity relationships.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anti-Bacterial Agents / chemical synthesis
Anti-Bacterial Agents / chemistry
Anti-Bacterial Agents / pharmacology*
Bacterial Proteins / antagonists & inhibitors*
Bacterial Proteins / metabolism
Dose-Response Relationship, Drug
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Gram-Negative Bacteria / drug effects*
Gram-Positive Bacteria / drug effects*
Microbial Sensitivity Tests
Molecular Conformation
Nucleosides / chemical synthesis
Nucleosides / chemistry
Nucleosides / pharmacology*
Structure-Activity Relationship
Transferases (Other Substituted Phosphate Groups)
Transferases / antagonists & inhibitors*
Transferases / metabolism

Substances

Anti-Bacterial Agents
Bacterial Proteins
Enzyme Inhibitors
Nucleosides
Transferases
Transferases (Other Substituted Phosphate Groups)
mraY protein, Bacteria