A Concise Synthetic Strategy Towards the Novel Calcium-dependent Lipopeptide Antibiotic, Malacidin A and Analogues

Nadiia Kovalenko; Georgina K Howard; Jonathan A Swain; Yann Hermant; Alan J Cameron; Gregory M Cook; Scott A Ferguson; Louise A Stubbing; Paul W R Harris; Margaret A Brimble

doi:10.3389/fchem.2021.687875

A Concise Synthetic Strategy Towards the Novel Calcium-dependent Lipopeptide Antibiotic, Malacidin A and Analogues

Front Chem. 2021 Aug 4:9:687875. doi: 10.3389/fchem.2021.687875. eCollection 2021.

Authors

Nadiia Kovalenko¹, Georgina K Howard¹, Jonathan A Swain¹, Yann Hermant¹, Alan J Cameron^{1

2

3}, Gregory M Cook^{3

4}, Scott A Ferguson⁴, Louise A Stubbing¹, Paul W R Harris^{1

2

3}, Margaret A Brimble^{1

2

3}

Affiliations

¹ School of Chemical Sciences, The University of Auckland, Auckland, New Zealand.
² School of Biological Sciences, The University of Auckland, Auckland, New Zealand.
³ Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland, New Zealand.
⁴ Department of Microbiology and Immunology, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand.

Abstract

Malacidin A is a novel calcium-dependent lipopeptide antibiotic with excellent activity against Gram-positive pathogens. Herein, a concise and robust synthetic route toward malacidin A is reported, employing 9-fluorenylmethoxycarbonyl solid-phase peptide synthesis of a linear precursor, including late-stage incorporation of the lipid tail, followed by solution-phase cyclization. The versatility of this synthetic strategy was further demonstrated by synthesis of a diastereomeric variant of malacidin A and a small library of simplified analogues with variation of the lipid moiety.

Keywords: antibiotic; antimicrobial; calcium-dependent; lipopeptide; solid-phase peptide synthesis.