Isolation and Structure of Platencin: A FabH and FabF Dual Inhibitor with Potent Broad‐Spectrum Antibiotic Activity

Jayasuriya, Hiranthi; Herath, Kithsiri; Zhang, Chaowei; Zink, Deborah L.; Basilio, Ángela; Genilloud, Olga; Dı́ez, Maria Teresa; Vicente, Francisca; González, Ignacio; Salazar, Óscar; Peláez, Fernando; Cummings, Richard; Ha, Sookhee; Wang, Jun; Singh, Sheo B.

doi:10.1002/anie.200701058

Cited by 186 publications

(139 citation statements)

References 24 publications

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“…The column was eluted with a step gradient of 40-100% aqueous methanol with 10% increments of MeOH. Two 600 ml fractions were collected from each 10% MeOH increments affording 14 fractions (Amberchrome fractions [1][2][3][4][5][6][7][8][9][10][11][12][13][14]. Amberchrome fractions 10-12 eluting with 80-90% MeOH were pooled and concentrated under reduced pressure, to remove most of the MeOH, to a volume of 200 ml mostly containing water.…”

Section: Isolation Of Platensimycin B 4 (3a) and Methyl Ester (3b)mentioning

confidence: 99%

“…[1][2][3][4] Discovery of these compounds was possible due to the design and introduction of a novel antisense differential sensitivity screening strategy in which FabH/FabF was sensitized. [3][4][5][6] Platensimycin is a selective inhibitor of the FabF acyl-enzyme intermediate and platencin is a balanced dual inhibitor of both FabH and FabF. Both of these compounds showed potent in vitro activities in both cell-free and whole-cell assay systems.…”

Section: Introductionmentioning

confidence: 99%

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Isolation, structure and biological activities of platensimycin B4 from Streptomyces platensis

et al. 2009

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Platensimycin and platencin are inhibitors of FabF and FabF/H bacterial fatty acid synthesis enzymes, respectively. Discovery of natural congeners provides one of the ways to understand the relationship of chemical structure and biological function. Efforts to discover the natural analogs of platensimycin by chemical screening led to the isolation of platensimycin B 4 , a glucoside congener of platensimycin. This analog showed significantly attenuated activity and critically defined the limited binding space around the aromatic ring and established the importance of the free phenolic and carboxyl group for the activity.

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Section: Isolation Of Platensimycin B 4 (3a) and Methyl Ester (3b)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Isolation, structure and biological activities of platensimycin B4 from Streptomyces platensis

et al. 2009

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“…-A Potent Thiazolyl Peptide Antibiotic from Amycolatopsis fastidiosa by new modes of action (e.g., platensimycin [3,4] and platencin [5,6]). …”

Section: Isolation and Structure Elucidation Of Thiazomycinmentioning

confidence: 99%

Isolation and Structure Elucidation of Thiazomycin

et al. 2007

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Thiazolyl peptides are a class of rigid macrocyclic compounds richly populated with thiazole rings. They are highly potent antibiotics but none have been advanced to clinic due to poor aqueous solubility. Recent progress in this field prompted a reinvestigation leading to the isolation of a new thiazolyl peptide, thiazomycin, a congener of nocathiacins. Thiazomycin possesses an oxazolidine ring as part of the amino-sugar moiety in contrast to the dimethyl amino group present in nocathiacin I. The presence of the oxazolidine ring provides additional opportunities for chemical modifications that are not possible with other nocathiacins. Thiazomycin is extremely potent against Gram-positive bacteria both in vitro and in vivo. The titer of thiazomycin in the fermentation broth was very low compared to the nocathiacins I and III. The lower titer together with its sandwiched order of elution presented significant challenges in large scale purification of thiazomycin. This problem was resolved by the development of an innovative preferential protonation based one-and/or two-step chromatographic method, which was used for pilot plant scale purifications of thiazomycin. The isolation and structure elucidation of thiazomycin is herein described.

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“…4 The combination of these two approaches resulted in the discovery of a large number of natural products using either an rpsD-sensitized antisense strain [5][6][7][8][9][10] or fabH/fabF antisense-sensitized strains, including discovery of the FabF inhibitors platensimycin and platencin. [11][12][13][14][15][16][17] Recently, we have extended the antisense-based screening approach by constructing a S. aureus genome-wide fitness test assay and validated its use by mechanistically profiling a diverse set of 59 antibacterial compounds 18 and by the discovery of a new class of cell wall inhibitors. 19 Included in the S. aureus fitness test assay are 245 inducible antisense RNA strains engineered for reduced expression of genes essential for cell growth.…”

Section: Introductionmentioning

confidence: 99%

Coelomycin, a highly substituted 2,6-dioxo-pyrazine fungal metabolite antibacterial agent discovered by Staphylococcus aureus fitness test profiling

et al. 2010

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Bacterial resistance to antibiotics, particularly to multiple antibiotics, is becoming a cause for significant concern. The only really viable course of action to counter this is to discover new antibiotics with novel modes of action. We have recently implemented a new antisense-based chemical genetic screening technology to accomplish this goal. The discovery and antibacterial activity of coelomycin, a fully substituted 2,6-dioxo pyrazine, illustrates the application of the Staphylococcus aureus fitness test strategy to natural products discovery.

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Isolation and Structure of Platencin: A FabH and FabF Dual Inhibitor with Potent Broad‐Spectrum Antibiotic Activity

Abstract: Two birds with one stone: Platencin (1) is a novel and potent broad‐spectrum Gram‐positive antibiotic. Whereas platensimycin is a selective inhibitor of FabF, platencin exerts its activity by a novel mode of action by dual inhibition of FabH and FabF.

Cited by 186 publications

References 24 publications

Isolation, structure and biological activities of platensimycin B4 from Streptomyces platensis

Isolation, structure and biological activities of platensimycin B4 from Streptomyces platensis

Isolation and Structure Elucidation of Thiazomycin

Coelomycin, a highly substituted 2,6-dioxo-pyrazine fungal metabolite antibacterial agent discovered by Staphylococcus aureus fitness test profiling

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