N1-(substituted) pantothenamides, antimetabolites of pantothenic acid

Clifton, Gil; Bryant, Sarah R.; Skinner, Charles G.

doi:10.1016/0003-9861(70)90470-4

Cited by 50 publications

(62 citation statements)

References 7 publications

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“…DISCUSSION We have shown that the pantothenamides inhibit bacterial growth through their incorporation into and inactivation of the ACP component of the type II fatty acid synthase system. The initial report of pantothenamide antibacterial activity suggested that this class of compounds interfered with pantothenate metabolism (15), and our data support this idea to some extent because the addition of pantothenate to the medium does render the cells somewhat more resistant to the pantothenamides (Fig. 2).…”

Section: Formation Of Faster Migrating Acps In Cells Treated With Thesupporting

confidence: 82%

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Acyl Carrier Protein Is a Cellular Target for the Antibacterial Action of the Pantothenamide Class of Pantothenate Antimetabolites

Zhang

Frank

Virga

et al. 2004

Journal of Biological Chemistry

124

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Pantothenate is the precursor of the essential cofactor coenzyme A (CoA). Pantothenate kinase (CoaA) catalyzes the first and regulatory step in the CoA biosynthetic pathway. The pantothenate analogs N-pentylpantothenamide and N-heptylpantothenamide possess antibiotic activity against Escherichia coli. Both compounds are substrates for E. coli CoaA and competitively inhibit the phosphorylation of pantothenate. The phosphorylated pantothenamides are further converted to CoA analogs, which were previously predicted to act as inhibitors of CoA-dependent enzymes. Here we show that the mechanism for the toxicity of the pantothenamides is due to the inhibition of fatty acid biosynthesis through the formation and accumulation of the inactive acyl carrier protein (ACP), which was easily observed as a faster migrating protein using conformationally sensitive gel electrophoresis. E. coli treated with the pantothenamides lost the ability to incorporate [1-14 C]acetate to its membrane lipids, indicative of the inhibition of fatty acid synthesis. Cellular CoA was maintained at the level sufficient for bacterial protein synthesis. Electrospray ionization time-of-flight mass spectrometry confirmed that the inactive ACP was the product of the transfer of the inactive phosphopantothenamide moiety of the CoA analog to apo-ACP, forming the ACP analog that lacks the sulfhydryl group for the attachment of acyl chains for fatty acid synthesis. Inactive ACP accumulated in pantothenamide-treated cells because of the active hydrolysis of regular ACP and the slow turnover of the inactive prosthetic group. Thus, the pantothenamides are pro-antibiotics that inhibit fatty acid synthesis and bacterial growth because of the covalent modification of ACP.CoA is the major acyl group carrier in living systems and is synthesized by a universal series of reactions beginning with the vitamin (B 5 ) pantothenate (1). All of the genes and enzymes involved in the CoA biosynthetic pathway have been identified in Escherichia coli (Fig. 1). The first step in the pathway is catalyzed by the key rate-controlling pantothenate kinase (CoaA) 1 (ATP:D-pantothenate 4Ј-phosphotransferase; EC 2.7.1.33). Cysteine is next added to the phosphopantothenate by 4Ј-phosphopantothenoylcysteine synthase and rapidly decarboxylated to phosphopantetheine. These two steps are carried out by a bifunctional polypeptide, phosphopantothenoylcysteine synthetase decarboxylase (denoted CoaBC, formally Dfp) (2). The last two steps are carried out by two separate enzymes, namely phosphopantetheine adenylyltransferase (CoaD) (3, 4) followed by the addition of the 3Ј-ribose phosphate by dephospho-CoA kinase (CoaE) (5). E. coli is capable of de novo pantothenate biosynthesis (1) or can import pantothenate from the medium via a sodium-dependent active transport process (6-8). CoA is also required for the synthesis of ACP, the acyl group carrier in bacterial fatty acid synthesis. The phosphopantetheine moiety of CoA is transferred to serine 36 of apo-ACP by [ACP]synthase (AcpS) (9, 10), and ...

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Section: Formation Of Faster Migrating Acps In Cells Treated With Thesupporting

confidence: 82%

“…1), that inhibit E. coli growth (15). These pantothenamides are substrates for CoaA, and the phosphorylated derivatives are used as substrates by CoaD and CoaE to produce the CoA analogs ethyldethia-CoA and butyldethia-CoA (16).…”

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confidence: 99%

Acyl Carrier Protein Is a Cellular Target for the Antibacterial Action of the Pantothenamide Class of Pantothenate Antimetabolites

Zhang

Frank

Virga

et al. 2004

Journal of Biological Chemistry

124

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“…4 Of these, pantothenamides are particularly interesting due to their antibacterial activity against S. aureus and E. coli. [5][6][7][8][9][10] Although the bacteriostatic effect of pantothenamides has been recognized since the 1950s, their exact mechanism of action in bacteria has only been clarified in the last 15 years. [5][6][7][8][9][10][11][12][13][14][15] Interestingly, pantothenamides are substrates of E. coli PanK (EcPanK).…”

Section: Introductionmentioning

confidence: 99%

Exploring structural motifs necessary for substrate binding in the active site of Escherichia coli pantothenate kinase

Awuah¹,

Ma²,

Hoegl³

et al. 2014

Bioorganic & Medicinal Chemistry

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The coenzyme A (CoA) biosynthetic enzymes have been used to produce various CoA analogues, including mechanistic probes of CoA-dependent enzymes such as those involved in fatty acid biosynthesis. These enzymes are also important for the activation of the pantothenamide class of antibacterial agents, and of a recently reported family of antibiotic resistance inhibitors. Herein we report a study on the selectivity of pantothenate kinase, the first and rate limiting step of CoA biosynthesis. A robust synthetic route was developed to allow rapid access to a small library of pantothenate analogs diversified at the β-alanine moiety, the carboxylate or the geminal dimethyl group. All derivatives were tested as substrates of Escherichia coli pantothenate kinase (EcPanK). Four derivatives, all N-aromatic pantothenamides, proved to be equivalent to the benchmark Npentylpantothenamide (N5-pan) as substrates of EcPanK, while two others, also with N-aromatic groups, were some of the best substrates reported for this enzyme. This collection of data provides insight for the future design of PanK substrates in the production of useful CoA analogues. Graphical abstractThe promiscuity of E. coli PanK has limits! We report the synthesis of pantothenate analogs diversified at the β-alanine moiety, the carboxylate or the geminal dimethyl group. Interestingly, some of these are among the best substrates reported for E. coli PanK.

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“…2 This ubiquitous cofactor is required for a diverse set of biological functions and is essential to all organisms. Most rely on the exogenous uptake of its natural precursor pantothenate (vitamin B 5 ), and extend it into CoA through a 5-step biotransformation. [3][4] The inherent differences in the CoA biosynthetic machinery between humans and microbial pathogens suggest that this pathway can be exploited for therapeutic applications.…”

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confidence: 99%

“…2 An important class of such compounds are the N-substituted pantothenamides, including the benchmark molecule in the field, N-pentylpantothenamide ( Figure 1). 5 This compound was shown to have potent activity against Escherichia coli (in low pantothenate media) 5 and Staphylococcus aureus. 6 It was later found that pantothenamides were, in fact, being extended by the CoA biosynthetic enzymes into CoA analogues which affected downstream targets such as the acyl carrier protein necessary for fatty acid synthesis.…”

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confidence: 99%

Stereochemical modification of geminal dialkyl substituents on pantothenamides alters antimicrobial activity

Hoegl¹,

Darabi²,

Tran³

et al. 2014

Bioorganic & Medicinal Chemistry Letters

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Pantothenamides are N-substituted pantothenate derivatives which are known to exert antimicrobial activity through interference with coenzyme A (CoA) biosynthesis or downstream CoA-utilizing proteins. A previous report has shown that replacement of the ProR methyl group of the benchmark N-pentylpantothenamide with an allyl group (R-anti configuration) yielded one of the most potent antibacterial pantothenamides reported so far (MIC of 3.2 μM for both sensitive and resistant Staphylococcus aureus). We describe herein a synthetic route for accessing the corresponding R-syn diastereomer using a key diastereoselective reduction with Baker's yeast, and report on the scope of this reaction for modified systems. Interestingly, whilst the R-anti diastereomer is the only one to show antibacterial activity, the R-syn isomer proved to be significantly more potent against the malaria parasite (IC 50 of 2.4 ± 0.2 μM). Our research underlines the striking influence that stereochemistry has on the biological activity of pantothenamides, and may find utility in the study of various CoA-utilizing systems. Keywordspantothenamides; antibacterial; antiplasmodial; baker's yeast; coenzyme A Infectious diseases remain a major contributing factor to worldwide mortality. Moreover, the development of antimicrobial resistance is raising significant concerns about the increasingly limited efficacy of currently available treatments. 1 There have been considerable efforts towards discovering and characterising novel therapeutic targets for antimicrobial drugs. One such target which has emerged as a promising point-of-attack is

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N1-(substituted) pantothenamides, antimetabolites of pantothenic acid

Cited by 50 publications

References 7 publications

Acyl Carrier Protein Is a Cellular Target for the Antibacterial Action of the Pantothenamide Class of Pantothenate Antimetabolites

Acyl Carrier Protein Is a Cellular Target for the Antibacterial Action of the Pantothenamide Class of Pantothenate Antimetabolites

Exploring structural motifs necessary for substrate binding in the active site of Escherichia coli pantothenate kinase

Stereochemical modification of geminal dialkyl substituents on pantothenamides alters antimicrobial activity

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