Isolation, structure and biological activities of platencin A2–A4 from Streptomyces platensis

Zhang, Chaowei; Ondeyka, John G.; Dietrich, Lisa; Gailliot, F. P.; Hesse, Michelle; Lester, Michael; Dorso, Karen; Motyl, Mary; Ha, Sookhee; Wang, Jun; Singh, Sheo B.

doi:10.1016/j.bmc.2010.02.030

Cited by 23 publications

(28 citation statements)

References 29 publications

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“…Initially, production titers of PTM and PTN ranged from 1 to 4 mg L −1 [15, 16], with later studies reporting up to 52 mg L −1 for PTM [30]. However, many of the natural congeners were isolated from fermentations as large as 3400 L at titers as low as 3 µg L −1 [24, 28, 29]. Semi-defined and chemically defined media for PTM production in S. platensis MA7327 have also been reported [53, 54].…”

Section: Impact Of Microbial Genomics On Ptm and Ptnmentioning

confidence: 99%

Platensimycin and platencin: Inspirations for chemistry, biology, enzymology, and medicine

Rudolf

Dong

Shen

2017

Biochemical Pharmacology

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Natural products have served as the main source of drugs and drug leads, and natural products produced by microorganisms are one of the most prevalent sources of clinical antibiotics. Their unparalleled structural and chemical diversities provide a basis to investigate fundamental biological processes while providing access to a tremendous amount of chemical space. There is a pressing need for novel antibiotics with new mode of actions to combat the growing challenge of multidrug resistant pathogens. This review begins with the pioneering discovery and biological activities of platensimycin (PTM) and platencin (PTN), two antibacterial natural products isolated from Streptomyces platensis. The elucidation of their unique biochemical mode of action, structure-activity relationships, and pharmacokinetics is presented to highlight key aspects of their biological activities. It then presents an overview of how microbial genomics has impacted the field of PTM and PTN and revealed paradigm-shifting discoveries in terpenoid biosynthesis, fatty acid metabolism, and antibiotic and antidiabetic therapies. It concludes with a discussion covering the future perspectives of PTM and PTN in regard to natural products discovery, bacterial diterpenoid biosynthesis, and the pharmaceutical promise of PTM and PTN as antibiotics and for the treatment of metabolic disorders. PTM and PTN have inspired new discoveries in chemistry, biology, enzymology, and medicine and will undoubtedly continue to do so.

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Section: Impact Of Microbial Genomics On Ptm and Ptnmentioning

confidence: 99%

Platensimycin and platencin: Inspirations for chemistry, biology, enzymology, and medicine

Rudolf

Dong

Shen

2017

Biochemical Pharmacology

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“…Analogues of PTM, PTN, and biosynthetic intermediates containing superfluous hydroxyl groups have been previously isolated. 11,15–17 Each of these analogues possessed an extra hydroxyl group on their diterpene-derived scaffold. This compound, however, appeared to have an unmodified ketolide as the electrospray ionization (ESI) MS spectrum showed a fragment ion at m/z 273, characteristic of the cleaved platensic acid, the ketolide of PTM (Fig.…”

Section: Resultsmentioning

confidence: 99%

Antibacterial sulfur-containing platensimycin and platencin congeners from Streptomyces platensis SB12029

Dong

Rudolf

Shen

2016

Bioorganic & Medicinal Chemistry

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The platensimycin (PTM) and platencin (PTN) class of natural products are promising drug leads that target bacterial and mammalian fatty acid synthases. Natural congeners and synthetic analogues of PTM and PTN have been instrumental in determining their structure-activity relationships, with only a few analogues retaining the potencies of PTM and PTN. Here we describe the identification and isolation of two new sulfur-containing PTM congeners (3 and 5) from the engineered dual PTM-PTN overproducing Streptomyces platensis SB12029. Structure elucidation of platensimycin D1 (5), a sulfur-containing PTM pseudo-dimer, revealed the existence of its presumptive thioacid precursor (3). The unstable thioacid 3 was isolated and confirmed by structural characterization of its permethylated product (6). LC-MS analysis of crude extracts of SB12029 confirmed the presence of the thioacid analogue of PTN (4). The minimum inhibitory concentration (MIC) was determined for 5 revealing retention of the strong antibacterial activity of PTM.

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“…In 2010, they isolated three hydroxylated analogs of platencin; that is, platencins A 2 , A 3 and A 4 from the broth of S. platensis MA7327. 36 These analogs were hydroxylated in the terpenoid portion of the molecule and were much less active than platencin.…”

Section: The Search For Analogs/derivatives Of Platensimycin and Platmentioning

confidence: 99%

Platensimycin and platencin: promising antibiotics for future application in human medicine

Martens

Demain

2011

J Antibiot

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Platensimycin and platencin are novel antibiotics produced by Streptomyces platensis. They are potent and non-toxic natural products active against Gram-positive pathogens, including antibiotic-resistant strains and Mycobacterium tuberculosis. They were isolated using an intriguing target-based whole-cell antisense differential sensitivity assay as inhibitors of fatty acid biosynthesis of type II. This type of biosynthesis is not present in humans. Platensimycin inhibits the elongation-condensing enzyme FabF, whereas platencin inhibits both FabF and FabH. For these antibiotics to become successful drugs, their pharmacokinetics must be improved. They have too high a rate of clearance in the body, yielding a low degree of systematic exposure. They work well when administered by continuous infusion, but this is not a useful method of delivery to patients. The two antibiotics and many analogs have been prepared by chemical synthesis. Natural congeners have also been obtained from the producing actinomycete. However, none of these molecules are as active as platensimycin and platencin. Using tools of rational metabolic engineering, superior strains have been produced making hundreds of times more antibiotic than the natural strains.

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Isolation, structure and biological activities of platencin A2–A4 from Streptomyces platensis

Cited by 23 publications

References 29 publications

Platensimycin and platencin: Inspirations for chemistry, biology, enzymology, and medicine

Platensimycin and platencin: Inspirations for chemistry, biology, enzymology, and medicine

Antibacterial sulfur-containing platensimycin and platencin congeners from Streptomyces platensis SB12029

Platensimycin and platencin: promising antibiotics for future application in human medicine

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