Inhibition of Daptomycin by Pulmonary Surfactant: In Vitro Modeling and Clinical Impact

Silverman, Jared; Mortin, Lawrence I.; VanPraagh, Andrew D. G.; Li, Tongchuan; Alder, Jeff

doi:10.1086/430352

Cited by 474 publications

(332 citation statements)

References 17 publications

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“…The likely cause for this discrepancy is the inhibition of daptomycin by lung surfactant, which binds and sequesters the drug. 21 The inhibition may be related to its content of phosphatidylglycerol (see section 10.1). Efforts have been made to develop daptomycin derivatives that avoid surfactant inhibition (see section 8.3).…”

Section: Antimicrobial Spectrum and Clinical Usementioning

confidence: 99%

The action mechanism of daptomycin

Taylor

Palmer

2016

Bioorganic & Medicinal Chemistry

220

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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Section: Antimicrobial Spectrum and Clinical Usementioning

confidence: 99%

The action mechanism of daptomycin

Taylor

Palmer

2016

Bioorganic & Medicinal Chemistry

220

172

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“…9 Daptomycin failed to meet noninferiority standards in a clinical trial for community-acquired pneumonia caused by Streptococcus pneumoniae, 10 apparently because it becomes sequestered in lung surfactant. 11 Many derivatives of A21978C have been made by chemical modifications of the lipid side chain or by additions to the d-amino group of ornithine (Orn 6 ), but none have yet proven superior to daptomycin. 12,13 A21978C and daptomycin are members of a family of acidic cyclic lipopeptide antibiotics with common evolutionary origins.…”

Section: Introductionmentioning

confidence: 99%

Genomics and the ancient origins of the daptomycin biosynthetic gene cluster

Baltz¹

2010

J Antibiot

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Daptomycin is a clinically useful lipopeptide antibiotic produced by Streptomyces roseosporus. The antibiotic is assembled by a nonribosomal peptide synthetase (NRPS) mechanism, and the cyclized tridecapeptide contains three non-proteinogenic L-amino acids: ornithine (Orn), 3-methyl-glutamic acid (3mGlu) and kynurinine (Kyn). Daptomycin also has three D-amino acids. The two genes that encode proteins involved in the formation of 3mGlu and Kyn have no known orthologs, and hence they are good probes to search for daptomycin-like gene clusters among newly sequenced actinomycete genomes. A recent search with these genes revealed a daptomycin-like gene cluster in Saccharomonospora viridis, a causative agent for farmer's lung disease. S. viridis has a genome of 4.3 Mb, which is about one half the size of Streptomyces genomes. Searches for other NRPS and polyketide synthase (PKS) genes revealed only one other NRPS gene and no PKS genes in S. viridis. The orthologous lipopeptide biosynthetic genes and gene products in S. viridis and S. roseosporus have diverged extensively from a last common ancestor dating back to a pathway that had evolved over 1 billion years ago.

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“…By comparison, the activity of daptomycin is much more readily antagonized by PG with 2.0 mol equiv, leading to complete loss of antibiotic action. Interestingly, PG is found in high concentrations in mammalian lung surfactant and is the likely cause of the ineffectiveness of daptomycin in treating lung infections 19. The effect of various biologically relevant phosphate monoesters on the activity of laspartomycin C was also investigated.…”

mentioning

confidence: 99%

A High‐Resolution Crystal Structure that Reveals Molecular Details of Target Recognition by the Calcium‐Dependent Lipopeptide Antibiotic Laspartomycin C

et al. 2017

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The calcium‐dependent antibiotics (CDAs) are an important emerging class of antibiotics. The crystal structure of the CDA laspartomycin C in complex with calcium and the ligand geranyl‐phosphate at a resolution of 1.28 Å is reported. This is the first crystal structure of a CDA bound to its bacterial target. The structure is also the first to be reported for an antibiotic that binds the essential bacterial phospholipid undecaprenyl phosphate (C55‐P). These structural insights are of great value in the design of antibiotics capable of exploiting this unique bacterial target.

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Inhibition of Daptomycin by Pulmonary Surfactant: In Vitro Modeling and Clinical Impact

Cited by 474 publications

References 17 publications

The action mechanism of daptomycin

The action mechanism of daptomycin

Genomics and the ancient origins of the daptomycin biosynthetic gene cluster

A High‐Resolution Crystal Structure that Reveals Molecular Details of Target Recognition by the Calcium‐Dependent Lipopeptide Antibiotic Laspartomycin C

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