Total Synthesis of Plusbacin A<sub>3</sub>: Depsipeptide Antibiotic Active Against Vancomycin‐Resistant Bacteria.

Wohlrab, Aaron; Lamer, Ryan; VanNieuwenhze, Michael S.

doi:10.1002/chin.200735182

Cited by 6 publications

(7 citation statements)

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“…Plusbacin A 3 has a structural motif commonly found in cyclic antimicrobial peptides: a cyclic-peptide core and a lipophilic side chain. 3 The cyclic core in plusbacin A 3 has eight amino acids cyclized through a lactone linkage between L-threo-β-hydroxyaspartic acid and a hydroxyl fatty acid subunit. The core is modified by attachment of an isotridecanyl side chain.…”

Section: ■ Introductionmentioning

confidence: 99%

Dual Mode of Action for Plusbacin A₃ in Staphylococcus aureus

et al. 2017

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We have used C{F}, N{F}, and N{P} rotational-echo double resonance NMR to determine the location and conformation of 19F and 15N double-labeled plusbacin A3 and of double-labeled deslipo-plusbacin A3, each bound to the cell walls of whole cells of Staphyloccocus aureus grown in media containing [1-13C]glycine. The 31P is primarily in wall teichoic acid. Approximately 25% of plusbacin headgroups (the cyclic depsipeptide backbone) are in a closed conformation (N–F separation of 6 Å), while 75% are in a more open conformation (N–F separation of 12 Å). The closed headgroups have no contact with wall teichoic acid, whereas the open headgroups have a strong contact. This places the closed headgroups in hydrophobic regions of the cell wall and the open headgroups in hydrophilic regions. None of the plusbacin tails have contact with the 31P of either wall teichoic acid or the cell membrane and thus are in hydrophobic regions of the cell wall. In addition, both heads and tails of plusbacin A3 have contact with the glycyl 13C incorporated in cell-wall peptidoglycan pentaglycyl bridges and with 13C-labeled purines near the membrane surface. We interpret these results in terms of a dual mode of action for plusbacin A3: first, disruption of the peptidoglycan layer nearest to the membrane surface by closed-conformation plusbacin A3 leading to an inhibition of chain extension by transglycosylation; second, thinning and disruption of the membrane (possibly including disruption of ATP-binding cassette transporters embedded in the membrane) by open-conformation plusbacin A3, thereby leading to release of ATP to the hydrophilic regions of the cell wall and subsequent binding by plusbacin A3.

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Section: ■ Introductionmentioning

confidence: 99%

Dual Mode of Action for Plusbacin A₃ in Staphylococcus aureus

et al. 2017

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“…The activity of pb-A 3 is antagonized by the addition of cell-wall membrane particulates, and its inhibition of nascent peptidoglycan biosynthesis in a cell membrane extract suggests that pb-A 3 , like vancomycin, may target the peptidoglycan precursor lipid II. 2,3 Unlike vancomycin, however, pb-A 3 is active against VRE and its activity is not affected by the addition of the tripeptide acetyl-L-Lys-D-Ala-D-Ala. 2 Thus, it appears that the binding site utilized by pb-A 3 is distinct from that of vancomycin.…”

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confidence: 99%

The Isotridecanyl Side Chain of Plusbacin-A₃ Is Essential for the Transglycosylase Inhibition of Peptidoglycan Biosynthesis

et al. 2013

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Plusbacin-A3 (pb-A3) is a cyclic lipodepsipeptide which exhibits antibacterial activity against multidrug-resistant Gram-positive pathogens. Plusbacin-A3 is thought not to enter the cell cytoplasm and its lipophilic isotridecanyl side chain is presumed to insert into the membrane bilayer thereby facilitating either lipid II binding or some form of membrane disruption. Analogues of pb-A3, [2H]pb-A3 and deslipo-pb-A3, were synthesized to test membrane insertion as key to the mode of action. [2H]pb-A3 has a 2H-isotopically labeled isopropyl subunit of the lipid side chain, and deslipo-pb-A3 is missing the isotridecanyl side chain. Both analogues have the pb-A3 core structure. The loss of antimicrobial activity in deslipo-pb-A3 showed that the isotridecanyl side chain is crucial for the drug mode of action. However, rotational-echo double resonance NMR characterization of [2H]pb-A3 bound to [1-13C]glycine labeled whole-cells of Staphylococcus aureus showed that the isotridecanyl side chain does not insert into the lipid membrane, but instead is found in the staphylococcal cell wall, positioned near the pentaglycyl cross-bridge of the cell-wall peptidoglycan. Addition of [2H]pb-A3 during S. aureus growth resulted in an accumulation of Park’s nucleotide, consistent with the inhibition of the transglycosylation step of peptidoglycan biosynthesis.

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“…xvi Sandoval et al, reported that (R)-3-hydroxy-n-phenylalkanoic acid had a significant antimicrobial effect against food pathogen such as Listeria monocytogenes present in the refrigerated food [33]. (R)-3-hydroxy-undecanoate is utilized for synthesis of depsipeptides (antibiotic/antifungal) [34]; lipid A mimic (immunobiological) [35]; (−)-tetrahydrolipstatin (antiobesity drug) [36]. (R)-3-hydroxyhexanoate is used for production of anti-microtubule agent such as analogs of laulimalide [37].…”

Section: Siv 231 Synthesis Of Chiral Compounds and Drugsmentioning

confidence: 99%

Polyhydroxyalkanoates – what are the uses? Current challenges and perspectives

Masood

Yasin

Hameed

2014

Critical Reviews in Biotechnology

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Over the past few decades, a considerable attention has been focused on the microbial polyhydroxyalkanoates (PHAs) owing to its multifaceted properties, i.e. biodegradability, biocompatibility, non-toxicity and thermo-plasticity. This article presents a critical review of the foregoing research, current trends and future perspectives on the value added applications of PHAs in the biomedical, environmental and industrial domains of life.

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Total Synthesis of Plusbacin A₃: Depsipeptide Antibiotic Active Against Vancomycin‐Resistant Bacteria.

Abstract: ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Cited by 6 publications

References 1 publication

Dual Mode of Action for Plusbacin A₃ in Staphylococcus aureus

Dual Mode of Action for Plusbacin A₃ in Staphylococcus aureus

The Isotridecanyl Side Chain of Plusbacin-A₃ Is Essential for the Transglycosylase Inhibition of Peptidoglycan Biosynthesis

Polyhydroxyalkanoates – what are the uses? Current challenges and perspectives

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Total Synthesis of Plusbacin A3: Depsipeptide Antibiotic Active Against Vancomycin‐Resistant Bacteria.

Abstract: ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Cited by 6 publications

References 1 publication

Dual Mode of Action for Plusbacin A3 in Staphylococcus aureus

Dual Mode of Action for Plusbacin A3 in Staphylococcus aureus

The Isotridecanyl Side Chain of Plusbacin-A3 Is Essential for the Transglycosylase Inhibition of Peptidoglycan Biosynthesis

Polyhydroxyalkanoates – what are the uses? Current challenges and perspectives

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Product

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Total Synthesis of Plusbacin A₃: Depsipeptide Antibiotic Active Against Vancomycin‐Resistant Bacteria.

Dual Mode of Action for Plusbacin A₃ in Staphylococcus aureus

Dual Mode of Action for Plusbacin A₃ in Staphylococcus aureus

The Isotridecanyl Side Chain of Plusbacin-A₃ Is Essential for the Transglycosylase Inhibition of Peptidoglycan Biosynthesis