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

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

doi:10.3389/fchem.2021.687875

Cited by 7 publications

(5 citation statements)

References 24 publications

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“…The final removal of acid‐labile t Bu/TBS side‐chain protecting groups was achieved using an optimized protocol of TFA/CH 2 Cl 2 /TIPS/H 2 O (50 : 45 : 2.5 : 2.5, v/v/v/v ) over 30 min to avoid acid‐mediated isomerization of the polyunsaturated lipid moiety. We were pleased to observe minimal isomerization under these conditions, given we had previously observed significant isomerization of the diene in the similar lipid motif of malacidin A with TFA [48] . Gratifyingly, in the present work, the TBS group was removed concurrently, thus eliminating the need for an additional deprotection step.…”

Section: Resultsmentioning

confidence: 71%

“…We were pleased to observe minimal isomerization under these conditions, given we had previously observed significant isomerization of the diene in the similar lipid motif of malacidin A with TFA. [48] Gratifyingly, in the present work, the TBS group was removed concurrently, thus eliminating the need for an additional deprotection step. The final crude peptide was purified by RP-HPLC to yield synthetic cadaside B (2 a) albeit in low 0.4 % yield (based on initial resin loading) over 34 steps.…”

Section: Chemistry-a European Journalmentioning

confidence: 94%

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Synthetic Studies towards the Calcium‐Dependent Lipopeptide Antibiotic Cadaside B

Kovalenko

Swain

Howard

et al. 2022

Chemistry A European J

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In the current global crisis of antimicrobial resistance, antimicrobial peptides represent a promising source of alternative antibiotics. Recently discovered cadaside B, a novel calcium-dependent antibiotic, exhibits potent antimicrobial activity towards Gram-positive pathogens including multi-drug resistant strains. These properties, coupled with a novel structure, non-cytotoxicity, and low likelihood of developing resistance render cadaside B an important synthetic target. Herein, a synthetic strategy towards cadaside B is reported with the key steps involving on-resin depsipeptide bond formation and solution-phase macrolactamization. Good agreement of the synthetic cadaside B MS/MS fragmentation pattern was observed with the natural product, but a different 1 H NMR spectrum and absence of antimicrobial activity suggest an undetected epimerization event took place during the synthesis. Herein the findings of our synthetic journey and suggestions for future directions are presented.

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Section: Resultsmentioning

confidence: 71%

Section: Chemistry-a European Journalmentioning

confidence: 94%

Synthetic Studies towards the Calcium‐Dependent Lipopeptide Antibiotic Cadaside B

Kovalenko

Swain

Howard

et al. 2022

Chemistry A European J

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“…These compounds were efficacious in an MRSA skin infection model and did not select for resistance under standard laboratory conditions. Recently, synthetic routes for malacidin have been described, paving the way for the synthesis of structurally diverse analogs to improve potency and pharmacokinetic properties [ 94 , 95 ].…”

Section: Natural Product Antibiotic Discoverymentioning

confidence: 99%

Returning to Nature for the Next Generation of Antimicrobial Therapeutics

MacNair¹,

Tsai

Rutherford³

et al. 2023

Antibiotics

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Antibiotics found in and inspired by nature are life-saving cures for bacterial infections and have enabled modern medicine. However, the rise in resistance necessitates the discovery and development of novel antibiotics and alternative treatment strategies to prevent the return to a pre-antibiotic era. Once again, nature can serve as a source for new therapies in the form of natural product antibiotics and microbiota-based therapies. Screening of soil bacteria, particularly actinomycetes, identified most of the antibiotics used in the clinic today, but the rediscovery of existing molecules prompted a shift away from natural product discovery. Next-generation sequencing technologies and bioinformatics advances have revealed the untapped metabolic potential harbored within the genomes of environmental microbes. In this review, we first highlight current strategies for mining this untapped chemical space, including approaches to activate silent biosynthetic gene clusters and in situ culturing methods. Next, we describe how using live microbes in microbiota-based therapies can simultaneously leverage many of the diverse antimicrobial mechanisms found in nature to treat disease and the impressive efficacy of fecal microbiome transplantation and bacterial consortia on infection. Nature-provided antibiotics are some of the most important drugs in human history, and new technologies and approaches show that nature will continue to offer valuable inspiration for the next generation of antibacterial therapeutics.

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“…Then in 2020, the complete synthesis of malacidin A was published by a joint group from the University of Hong Kong and Rockefeller [ 46 ]. As a result of the malacidin findings, a second total synthesis of malacidin A and analogues was recently published by the Brimble group in New Zealand [ 47 ].…”

Section: Other Peptide-based Antibiotic Classes With Potentialmentioning

confidence: 99%

Old and Modern Antibiotic Structures with Potential for Today’s Infections

Newman¹

2022

ADMET DMPK

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Due to the lack of new antibiotics with efficacy against the ESKAPE and other resistant microbes, coupled to the demise of major pharmaceutical company antibiotic discovery programs, due to a number of factors but mainly ROI calculations and the lack of efficacy of combinatorial chemistry as a substitute, the search for novel antibiotics may well have moved to the utilization of older structures with significant synthetic chemistry input. This short review demonstrates how modern synthetic chemistry, when applied to either modification of current resistant antibiotics such as glycopeptides, or production of novel peptidic agents based on natural product sourced antimicrobial peptides (AMPs) and other potential initial peptide-based agents from genomic searches and baiting techniques, have produced active agents of significant utility. In addition, synthetic chemistry practitioners have now shown that they can produce bioactive molecules of greater than 800 Daltons in kilogram quantities under cGMP conditions.

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

Cited by 7 publications

References 24 publications

Synthetic Studies towards the Calcium‐Dependent Lipopeptide Antibiotic Cadaside B

Synthetic Studies towards the Calcium‐Dependent Lipopeptide Antibiotic Cadaside B

Returning to Nature for the Next Generation of Antimicrobial Therapeutics

Old and Modern Antibiotic Structures with Potential for Today’s Infections

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