Synthesis and biological activity of N-Acylated ornithine analogues of daptomycin

Hill, Jason M.; Siedlecki, James M.; Parr, Ian B.; Morytko, Michael; Xiang, Yu; Zhang, Yanzhi; Silverman, Jared; Controneo, Nicole; Laganas, Valerie A.; Li, Tongchuan; Lai, Jan‐Ji; Keith, Dennis D.; Shimer, George H.; Finn, John M.

doi:10.1016/j.bmcl.2003.07.019

Cited by 50 publications

(71 citation statements)

References 7 publications

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“…The significant structural diversity already generated can be further expanded by medicinal chemistry toward an even larger set of molecules to explore as potential candidates for clinical development: e.g., more extensive substitutions of the fatty acid tail, which previous studies have shown can have a pronounced effect on potency and toxicity of daptomycin related lipopeptides (2,3,10), and modifications of the amino and hydroxyl groups of the introduced residues such as D-Lys 8 and D-Ser 8 , respectively. Introduction of modules specific for modified amino acids together with their tailoring enzymes (e.g., hydroxylase and methyltransferase for Asp) would provide additional options to generate diversity.…”

Section: Discussionmentioning

confidence: 99%

“…A number of semisynthetic derivatives of daptomycin that contained modified lipid tails or side chains coupled through the ␦-amino group of ornithine (Orn 6 ) were synthesized, but they represented limited structural diversity, and none had improved pharmacological properties (3,10). Attempts to synthesize daptomycin derivatives with changes in the amino acid core by chemical (I. Parr, personal communication) and chemoenzymatic (11) methods have been hampered by the lack of commercially available 3-methyl-glutamic acid (for 3mGlu 12 ).…”

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confidence: 99%

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Combinatorial biosynthesis of novel antibiotics related to daptomycin

Nguyen

Ritz

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

258

239

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Daptomycin, a cyclic lipopeptide produced by Streptomyces roseosporus, is the active ingredient of Cubicin (daptomycin-forinjection), a first-in-class antibiotic approved for treatment of skin and skin-structure infections caused by Gram-positive pathogens and bacteremia and endocarditis caused by Staphylococcus aureus, including methicillin-resistant strains. Genetic engineering of the nonribosomal peptide synthetase (NRPS) in the daptomycin biosynthetic pathway was exploited for the biosynthesis of novel active antibiotics. -Red-mediated recombination was used to exchange single or multiple modules in the DptBC subunit of the NRPS to modify the daptomycin cyclic peptide core. We combined module exchanges, NRPS subunit exchanges, inactivation of the tailoring enzyme glutamic acid 3-methyltransferase, and natural variations of the lipid tail to generate a library of novel lipopeptides, some of which were as active as daptomycin against Grampositive bacteria. One compound was more potent against an Escherichia coli imp mutant that has increased outer membrane permeability. This study established a robust combinatorial biosynthesis platform to produce novel peptide antibiotics in sufficient quantities for antimicrobial screening and drug development.cubicin ͉ genetic engineering ͉ nonribosomal peptide ͉ Streptomyces

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Combinatorial biosynthesis of novel antibiotics related to daptomycin

Nguyen

Ritz

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

258

239

View full text Add to dashboard Cite

show abstract

“…55 In 56,57 The amino group was found not to be essential for antibac-terial activity as many of these analogues retained good biological activity though retention of at least one NH proton in the derivatized Orn side-chain was important for retaining potency. The role of the amino group in the mode of action is unknown.…”

Section: Functional Effects Of Single or Combined Amino Acid Substitumentioning

confidence: 99%

The action mechanism of daptomycin

Taylor

Palmer

2016

Bioorganic & Medicinal Chemistry

237

172

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Daptomycin is a lipopeptide antibiotic produced by the soil bacterium Streptomyces roseosporus that is clinically used to treat severe infections with Grampositive bacteria. In this review, we discuss the mode of action of this important antibiotic. Although daptomycin is structurally related to amphomycin and similar lipopeptides that inhibit peptidoglycan biosynthesis, experimental studies have not produced clear evidence that daptomycin shares their action mechanism. Instead, the best characterized effect of daptomycin is the permeabilization and depolarization of the bacterial cell membrane. This activity, which can account for daptomycin's bactericidal effect, correlates with the level of phosphatidylglycerol (PG) in the membrane. Accordingly, reduced synthesis of PG or its increased conversion to lysyl-PG promotes bacterial resistance to daptomycin. While other resistance mechanisms suggest that daptomycin may indeed directly interfere with cell wall synthesis or cell division, such effects still await direct experimental confirmation. Daptomycin's complex structure and biosynthesis have hampered the analysis of its structure activity relationships. Novel methods of total synthesis, including a recent one that is carried out entirely on a solid phase, will enable a more thorough and systematic exploration of the sequence space.

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“…Like A21987C and daptomycin, 3,4 the Nterminal Trp 1 of the exocyclic peptide is coupled to long-chain length fatty acids, the most common being iso-decanoyl, n-decanoyl and anteiso-undecanoyl in A54145 factors. 1,2 A54145 factors also vary at positions 12 and 13, in which different factors have different combinations of Glu 12 , L-3-methyl-Glu 12 (3mGlu 12 ), Ile 13 , or Val 13 . The most prevalent factors produced during the S. fradiae fermentation are shown in Figure 1.…”

Section: A54145 (mentioning

confidence: 99%

“…7 Several semisynthetic derivatives were tested for antibacterial properties and acute toxicity in mice. 8 The most potent natural factors (B, B 1 and E), contain 3mGlu 12 and Ile 13 , but the LD 50 for A54145B is low at only 28 mg kg À1 . The natural factors containing Glu 12 and Ile 13 had about twofold lower antibacterial activities, but were substantially less toxic (for example, LD 50 4500 mg kg À1 for A54145A).…”

Section: A54145 (mentioning

confidence: 99%

Production of novel lipopeptide antibiotics related to A54145 by Streptomyces fradiae mutants blocked in biosynthesis of modified amino acids and assignment of lptJ, lptK and lptL gene functions

Alexander

Rock

et al. 2010

J Antibiot

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A54145 is a complex of lipopeptide antibiotics produced by Streptomyces fradiae. A54145 factors are structurally related to daptomycin, with four modified amino acids, only one of which is present in daptomycin. We generated three mutants defective in lptJ, lptK or lptL, whose gene products are involved in the formation of hydroxy-Asn 3 (hAsn 3 ) and methoxy-Asp 9 (moAsp 9 ). Each of the mutants produced novel lipopeptides related to A54145 and the profiles allowed assignment of functions for those genes. We constructed strains carrying different combinations of these genes coupled with a mutation in the lptI gene involved in the biosynthesis of 3-methyl-Glu 12 (3mGlu 12 ), and all recombinants produced novel lipopeptides. One of the compounds displayed very good antibacterial activity in the presence of bovine surfactant, which interacts with daptomycin or A54145E to inhibit their antibacterial activities. (Figure 1) is a complex of calcium-dependent lipodepsipeptide antibiotics produced by Streptomyces fradiae NRRL 18160. 1,2 A54145 has a cyclic depsipeptide ring containing 10 amino acids and an exocyclic tail of three amino acids, and it is similar in overall structure to daptomycin. Like A21987C and daptomycin, 3,4 the Nterminal Trp 1 of the exocyclic peptide is coupled to long-chain length fatty acids, the most common being iso-decanoyl, n-decanoyl and anteiso-undecanoyl in A54145 factors. 1,2 A54145 factors also vary at positions 12 and 13, in which different factors have different combinations of Glu 12 , L-3-methyl-Glu 12 (3mGlu 12 ), Ile 13 , or Val 13 . The most prevalent factors produced during the S. fradiae fermentation are shown in Figure 1. Typically, A54145 factors containing Glu 12 accumulate early in fermentation and those containing 3mGlu 12 accumulate later, with final yields of about 60% of factors containing Glu 12 . 1 The study by Boeck et al. 5 demonstrated that the distribution of A54145 factors can be manipulated by adding certain amino acids or lipids to the fermentation. For instance, feeding L-Ile, enriched for factors containing Ile 13 from 89 to 98%, whereas feeding L-Val (which inhibited overall lipopeptide production by about 70%) enriched for compounds containing Val 13 from 11 to 56%, almost exclusively in

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Synthesis and biological activity of N-Acylated ornithine analogues of daptomycin

Cited by 50 publications

References 7 publications

Combinatorial biosynthesis of novel antibiotics related to daptomycin

Combinatorial biosynthesis of novel antibiotics related to daptomycin

The action mechanism of daptomycin

Production of novel lipopeptide antibiotics related to A54145 by Streptomyces fradiae mutants blocked in biosynthesis of modified amino acids and assignment of lptJ, lptK and lptL gene functions

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