CJ-15,801, a Novel Antibiotic from a Fungus, Seimatosporium sp.

Sugie, Yutaka; Dekker, Koen; Hirai, Hideo; Ichiba, Toshio; Ishiguro, Masaru; Shioni, Yukio; Brennan, Lori; Duignan, Joan; Huang, Liang H.; Sutcliffe, Joyce A.; Kojima, Yasuhiro

doi:10.7164/antibiotics.54.1060

Cited by 41 publications

(28 citation statements)

References 8 publications

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“…The original Pfizer discovery group found that in standard susceptibility tests conducted using cation adjusted Mueller-Hinton broth as growth medium CJ-15,801 is uniquely and peculiarly selective for S. aureus , with none of the other organisms tested showing inhibition at 100 μg/mL (460 μM) (Sugie, et al, 2001). These resistant organisms included both Gram-positive ( Staphylococcus , Enterococcus and Streptococcus spp. )…”

Section: Resultsmentioning

confidence: 99%

“…(Sugie, et al, 2001), provoked curiosity in regards to its mechanism of action. Here we show that the primary reason for this selectivity is the substrate specificity of the host organism’s PanK enzyme.…”

Section: Discussionmentioning

confidence: 99%

“…fungus (Sugie, et al, 2001). Structural analysis showed the compound to resemble pantothenic acid (vitamin B 5 , 2 ; Figure 1B), the natural precursor of the essential metabolic cofactor coenzyme A (CoA, 3 ) (Strauss, 2010), with the notable exception of a trans -substituted double bond in the β-alanine moiety.…”

Section: Introductionmentioning

confidence: 99%

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The Antibiotic CJ-15,801 Is an Antimetabolite that Hijacks and Then Inhibits CoA Biosynthesis

Westhuyzen

Hammons

Meier

et al. 2012

Chemistry & Biology

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SUMMARY The natural product CJ-15,801 is an inhibitor of Staphylococcus aureus, but not other bacteria. Its close structural resemblance to pantothenic acid, the vitamin precursor of coenzyme A (CoA), and its Michael acceptor moiety suggest that it irreversibly inhibits an enzyme involved in CoA biosynthesis or utilization. However, its mode of action and the basis for its specificity have not been elucidated to date. We demonstrate that CJ-15,801 is transformed by the uniquely selective S. aureus pantothenate kinase, the first CoA biosynthetic enzyme, into a substrate for the next enzyme, phosphopantothenoylcysteine synthetase, which is inhibited through formation of a tight-binding structural mimic of its native reaction intermediate. These findings reveal CJ-15,801 as a vitamin biosynthetic pathway antimetabolite with a mechanism similar to that of the sulfonamide antibiotics, and highlight CoA biosynthesis as a viable antimicrobial drug target.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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The Antibiotic CJ-15,801 Is an Antimetabolite that Hijacks and Then Inhibits CoA Biosynthesis

Westhuyzen

Hammons

Meier

et al. 2012

Chemistry & Biology

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“…Another, CJ-15,801 [150] (Fig. (13B)), is a recently isolated [151] fungal metabolite. A number of other analogues have also been synthesised [148].…”

Section: Pantothenate Analogues As Potential Antimalarialsmentioning

confidence: 99%

Mitochondrial Drug Targets in Apicomplexan Parasites

Mather¹,

Henry²,

Vaidya³

2007

CDT

108

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In evolutionary terms, mitochondria in apicomplexan parasites appear to be "relicts-in-the-making": they possess the smallest mitochondrial genomes known, encoding only three proteins, and in one genus, Cryptosporidium, the genome is eliminated altogether. Several features of mitochondrial physiology provide validated or potential targets for antiparasitic drugs. Atovaquone, a broad spectrum antiparasitic drug, selectively inhibits mitochondrial electron transport at the cytochrome bc(1) complex and collapses mitochondrial membrane potential. Recent investigations using model systems provide important insights into the mechanism of action for this drug, which may prove valuable for development of other selective inhibitors of mitochondrial electron transport. Although mitochondria do not appear to be a source of ATP during the erythrocytic stages in Plasmodium species, they do serve other critical functions, including the assembly of iron-sulfur clusters and various other biosynthetic processes depending on the species. To serve these metabolic functions, parasites need to maintain the apparatus for mitochondrial genome replication, repair, recombination, transcription, and translation, components of which are encoded in the nucleus and imported into the mitochondrion. Several unusual aspects of the components of this apparatus are coming to light through genome sequence analyses, and could provide potential targets for antiparasitic drug discovery and development.

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“…Thus, diversity exists amongst the structures and properties of pantothenate kinases, and these essential enzymes have become attractive drug targets for the development of novel antimicrobial agents (5, 13, 17). N-substituted pantothenamides ( N -pentylpantothenamide and N -heptylpantothenamide) and CJ-15,801 produced by Seimatosporium sp., which have the ability to inhibit the prokaryotic type II CoaA, have been shown to effectively interfere with the growth of Staphylococcus aureus , which uses the type II CoaA in its CoA biosynthetic pathway (4, 11, 18, 20, 21). …”

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confidence: 99%

Antimicrobial Activity of Pantothenol against Staphylococci Possessing a Prokaryotic Type II Pantothenate Kinase

et al. 2014

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Pantothenol is a provitamin of pantothenic acid (vitamin B5) that is widely used in healthcare and cosmetic products. This analog of pantothenate has been shown to markedly inhibit the phosphorylation activity of the prokaryotic type II pantothenate kinase of Staphylococcus aureus, which catalyzes the first step of the coenzyme A biosynthetic pathway. Since type II enzymes are found exclusively in staphylococci, pantothenol suppresses the growth of S. aureus, S. epidermidis, and S. saprophyticus, which inhabit the skin of humans. Therefore, the addition of this provitamin to ointment and skincare products may be highly effective in preventing infections by opportunistic pathogens.

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CJ-15,801, a Novel Antibiotic from a Fungus, Seimatosporium sp.

Cited by 41 publications

References 8 publications

The Antibiotic CJ-15,801 Is an Antimetabolite that Hijacks and Then Inhibits CoA Biosynthesis

The Antibiotic CJ-15,801 Is an Antimetabolite that Hijacks and Then Inhibits CoA Biosynthesis

Mitochondrial Drug Targets in Apicomplexan Parasites

Antimicrobial Activity of Pantothenol against Staphylococci Possessing a Prokaryotic Type II Pantothenate Kinase

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