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

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

doi:10.3389/fchem.2021.687875

Nadiia Kovalenko, Yann Hermant + Show 8 more

Open Access

https://doi.org/10.3389/fchem.2021.687875

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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.

Highlights

The present COVID-19 pandemic shows how vulnerable society is to an infectious disease without access to an immediate effective treatment
According to World Health Organization (WHO) reports, as many as 2.8 million people contract infections caused by antimicrobial resistance (AMR) pathogens in the U.S alone, leading to more than 35,000 deaths annually (Centers for Disease Control and Prevention (U.S.), 2019; World Health Organization, 2019)
New stewardship programs and policies to increase AMR awareness and limit the use of existing antimicrobials are being introduced around the world, the existing clinical pipeline does not meet the demand to effectively combat increasing rates of AMR infections (World Health Organization, 2015)

Summary

Introduction

The present COVID-19 pandemic shows how vulnerable society is to an infectious disease without access to an immediate effective treatment. Peptides 1b-1e were prepared in 2–6% overall yields with variation at residue positions 2 and 5, employing appropriately protected derivatives of (2S,3S)- or (2S,3R)-3-MeDap, and (2S,3S)- or (2S,3R)-3-HyAsp, respectively. Before synthesis of the diastereomer of malacidin A (1a) could commence, appropriately protected building blocks of (2S,3S)-3MeAsp1, (2S,3S)-3-MeDap2, (2S,3S)-3-HyAsp5, (2R,3R)-3MeAsp8 and (2S,4R)-4-MePro10 and (2E,4Z)-8-methylnona2,4-dienoic acid were required to facilitate incorporation using solid-phase synthesis.

Results

Conclusion