A Decade of Research on Daptomycin

Taylor, Scott D.

doi:10.1055/a-1885-4934

Cited by 3 publications

(3 citation statements)

References 43 publications

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“…A number of methods to access daptomycin or analogues via chemical synthesis have been reported. 7,9–12,17,18 Our group recently reported a Boc solid-phase peptide synthesis (SPPS) for daptomycin that employs an on-resin reductive ozonolysis step to convert Trp13 to the requisite Kyn13. 9 This transformation mitigated the need to acylate the Thr4 alcohol with the Kyn13 carboxylic acid which proved challenging in our hands, and others.…”

Section: Resultsmentioning

confidence: 99%

“…1, green). Our group, and others, have experienced many hurdles to form the depsipeptide bonds present in the natural products daptomycin, 9–12 YM-280193, 13 cadaside B, 14 brevicidine and laterocidine. 15,16 In each case, a series of reaction conditions were screened in order to achieve an acceptable level of conversion to the depsipeptide bond, or a significantly long reaction time was required.…”

Section: Introductionmentioning

confidence: 99%

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Factors influencing on-resin depsipeptide bond formation: case studies on daptomycin- and brevicidine-derived sequences

et al. 2023

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Factors influencing on-resin depsipeptide bond formation: case studies on daptomycin- and brevicidine-derived sequences

et al. 2023

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“…Taromycin A is recognized immediately as a marine-derived cognate structure of the Gram-positive antibiotic, daptomycin [ 84 , 85 ]. Daptomycin interferes with bacterial peptidoglycan biosynthesis by complexation with its biosynthetic intermediates [ 86 , 87 ]. Daptomycin is used increasingly in the clinic against serious Gram-positive bacterial infections.…”

Section: Do Marine Organisms Biosynthesize Exceptional Inhibitors Of ...mentioning

confidence: 99%

β-Lactams from the Ocean

Fisher

Mobashery

2023

Marine Drugs

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The title of this essay is as much a question as it is a statement. The discovery of the β-lactam antibiotics—including penicillins, cephalosporins, and carbapenems—as largely (if not exclusively) secondary metabolites of terrestrial fungi and bacteria, transformed modern medicine. The antibiotic β-lactams inactivate essential enzymes of bacterial cell-wall biosynthesis. Moreover, the ability of the β-lactams to function as enzyme inhibitors is of such great medical value, that inhibitors of the enzymes which degrade hydrolytically the β-lactams, the β-lactamases, have equal value. Given this privileged status for the β-lactam ring, it is therefore a disappointment that the exemplification of this ring in marine secondary metabolites is sparse. It may be that biologically active marine β-lactams are there, and simply have yet to be encountered. In this report, we posit a second explanation: that the value of the β-lactam to secure an ecological advantage in the marine environment might be compromised by its close structural similarity to the β-lactones of quorum sensing. The steric and reactivity similarities between the β-lactams and the β-lactones represent an outside-of-the-box opportunity for correlating new structures and new enzyme targets for the discovery of compelling biological activities.

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Chemoenzymatic Modification of Daptomycin: Aromatic Group Installation on Trp1

Dimas,

Kumar,

Mandal

et al. 2024

ChemBioChem

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Daptomycin is a cyclic lipodepsipeptide antibiotic used to treat infections caused by Gram‐positive pathogens, including multi‐drug resistant strains such as methicillin‐resistant Staphylococcus au‐reus (MRSA) and vancomycin‐resistant enterococci (VRE). The emergence of daptomycin‐resistant bacterial strains has renewed interest in generating daptomycin analogs. Previous studies have shown that replacing the tryptophan of daptomycin with aromatic groups can generate analogs with enhanced potency. Additionally, we have demonstrated that aromatic prenyltransferases can attach diverse groups to the tryptophan of daptomycin. Here, we report the use of the prenyltransferase CdpNPT to derivatize the tryptophan of daptomycin with a library of benzylic and heterocyclic pyrophosphates. An analytical‐scale study revealed that CdpNPT can transfer various aromatic groups onto daptomycin. Subsequent scaled‐up and purified reactions indicated that the enzyme can attach aromatic groups to N1, C2, C5 and C6 positions of Trp1 of daptomycin. In vitro antibacterial activity assays using six of these purified compounds identified aromatic substituted daptomycin analogs show potency against both daptomycin‐susceptible and resistant strains of Gram‐positive bacteria. These findings suggest that installing aromatic groups on the Trp1 of daptomycin can lead to the generation of potent daptomycin analogs.

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A Decade of Research on Daptomycin

Cited by 3 publications

References 43 publications

Factors influencing on-resin depsipeptide bond formation: case studies on daptomycin- and brevicidine-derived sequences

Factors influencing on-resin depsipeptide bond formation: case studies on daptomycin- and brevicidine-derived sequences

β-Lactams from the Ocean

Chemoenzymatic Modification of Daptomycin: Aromatic Group Installation on Trp1

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