Total Synthesis of Micrococcin P1 through Scalable Thiazole Forming Reactions of Cysteine Derivatives and Nitriles

Christy, Mitchell P.; Johnson, Trevor; McNerlin, Clare; Woodard, John L.; Nelson, Andrew T.; Lim, Bryant; Hamilton, Tiffany L; Freiberg, Kaitlyn M; Siegel, Dionicio

doi:10.1021/acs.orglett.0c00202

Cited by 17 publications

(13 citation statements)

References 52 publications

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“…As a result other groups have sought to develop a micrococcin P1 nanoparticle formula to circumvent its poor pharmacokinetics ( Liu et al, 2020 ). Another group has recently reported the total laboratory synthesis of micrococcin P1 through a scalable thiazole forming sequence that produced synthetic micrococcin that was spectroscopically and functionally indistinguishable from the natural product ( Christy et al, 2020 ). Here, we show that micrococcin P1 can also be extracted from bacterial culture supernatant using n-butanol.…”

Section: Discussionmentioning

confidence: 99%

Antimicrobials from a feline commensal bacterium inhibit skin infection by drug-resistant S. pseudintermedius

O’Neill

Worthing

Kulkarni

et al. 2021

eLife

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Methicillin-resistant Staphylococcus pseudintermedius (MRSP) is an important emerging zoonotic pathogen that causes severe skin infections. To combat infections from drug-resistant bacteria, the transplantation of commensal antimicrobial bacteria as a therapeutic has shown clinical promise. We screened a collection of diverse staphylococcus species from domestic dogs and cats for antimicrobial activity against MRSP. A unique strain (S. felis C4) was isolated from feline skin that inhibited MRSP and multiple gram-positive pathogens. Whole genome sequencing and mass spectrometry revealed several secreted antimicrobials including a thiopeptide bacteriocin micrococcin P1 and phenol-soluble modulin beta (PSMβ) peptides that exhibited antimicrobial and anti-inflammatory activity. Fluorescence and electron microscopy revealed that S. felis antimicrobials inhibited translation and disrupted bacterial but not eukaryotic cell membranes. Competition experiments in mice showed that S. felis significantly reduced MRSP skin colonization and an antimicrobial extract from S. felis significantly reduced necrotic skin injury from MRSP infection. These findings indicate a feline commensal bacterium that could be utilized in bacteriotherapy against difficult-to-treat animal and human skin infections.

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Section: Discussionmentioning

confidence: 99%

Antimicrobials from a feline commensal bacterium inhibit skin infection by drug-resistant S. pseudintermedius

O’Neill

Worthing

Kulkarni

et al. 2021

eLife

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“…Lastly, total synthesis of thiopeptides as a way to gain complete atomic-level control over a compound should be mentioned. The exquisite structural complexity of thiopeptides consistently attracts attention of the synthetic community: the first thiopeptide total synthesis, that of promothiocin A, was completed in 1998 (Moody and Bagley, 1998), and more than two decades later new approaches are still being actively pursued (Akasapu et al, 2019;Christy et al, 2020). Continued development of synthetic methodology and planning eventually yielded total synthesis of complex bimacrocyclic architectures of thiostrepton (Nicolaou et al, 2005a), siomycin (Mori et al, 2008), and, more recently, nosiheptide (Wojtas et al, 2016).…”

Section: Reviewmentioning

confidence: 99%

Introduction to Thiopeptides: Biological Activity, Biosynthesis, and Strategies for Functional Reprogramming

Vinogradov

Suga

2020

Cell Chemical Biology

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Thiopeptides (also known as thiazolyl peptides) are structurally complex natural products with rich biological activities. Known for over 70 years for potent killing of Gram-positive bacteria, thiopeptides are experiencing a resurgence of interest in the last decade, primarily brought about by the genomic revolution of the 21st century. Every area of thiopeptide research-from elucidating their biological function and biosynthesis to expanding their structural diversity through genome mining-has made great strides in recent years. These advances lay the foundation for and inspire novel strategies for thiopeptide engineering. Accordingly, a number of diverse approaches are being actively pursued in the hope of developing the next generation of naturalproduct-inspired therapeutics. Here, we review the contemporary understanding of thiopeptide biological activities, biosynthetic pathways, and approaches to structural and functional reprogramming, with a special focus on the latter.

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“…In our group, we have succeeded synthesizing micrococcin P1 implementing cysteine nitrile condensation reactions to form thiazoles. 18 This provided guidance in the synthesis of the common core of the 26-membered thiopeptides that we believe to be a fundamentally important substrate to assess structure-activity relationships present in this class of natural products as they are related to antiproliferative effects.…”

Section: Feature Synthesismentioning

confidence: 99%

Synthesis of the 26-Membered Core of Thiopeptide Natural Products by Scalable Thiazole-Forming Reactions of Cysteine Derivatives and Nitriles

2020

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The increased resistance of bacteria to clinical antibiotics is one of the major dilemmas facing human health and without solutions the problem will grow exponentially worse. Thiopeptide natural products have shown promising antibiotic activities and provide an opportunity for the development of a new class of antibiotics. Attempts to directly translate these compounds into human medicine have been limited due to poor physiochemical properties. The synthesis of the core structure of the 26-membered class of thiopeptide natural products is reported using chemistry that enables the synthesis of large quantities of synthetic intermediates and the common core structure. The use of cysteine/nitrile condensation reactions followed by oxidation to generate thiazoles has been key in enabling large academic scale reactions that in many instances avoided chromatography further aiding in accessing large amounts of key synthetic intermediates.

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Total Synthesis of Micrococcin P1 through Scalable Thiazole Forming Reactions of Cysteine Derivatives and Nitriles

Cited by 17 publications

References 52 publications

Antimicrobials from a feline commensal bacterium inhibit skin infection by drug-resistant S. pseudintermedius

Antimicrobials from a feline commensal bacterium inhibit skin infection by drug-resistant S. pseudintermedius

Introduction to Thiopeptides: Biological Activity, Biosynthesis, and Strategies for Functional Reprogramming

Synthesis of the 26-Membered Core of Thiopeptide Natural Products by Scalable Thiazole-Forming Reactions of Cysteine Derivatives and Nitriles

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