Structures of ClpC1-NTD with potent anti-TB cyclic peptides Rufomycin and Ecumicin: implications for the mechanism of action and design of therapeutic agents

Wolf, Nina M.; Lee, Hyun; Nam, Joo‐Won; Hong, Jeongpyo; Duc, Nguyen Minh; Ho, Ngo Anh; Lee, Hanki; Suh，Joo-Won,; Pauli, Guido F.; Franzblau, Scott G.; Cho, Sang Hyun; Abad‐Zapatero, Celerino

doi:10.1107/s0108767319099409

Cited by 2 publications

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“…HR37v), similar to that of rifampicin [199]. The anti-tuberculosis activity results from the binding of the peptides to the N-terminal domain of the bacterial protease-associated unfoldase ClpC1, resulting in cell death [192,200].…”

Section: Bacteria-produced Cyclic Peptidesmentioning

confidence: 96%

Marine Cyclic Peptides: Antimicrobial Activity and Synthetic Strategies

et al. 2022

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Oceans are a rich source of structurally unique bioactive compounds from the perspective of potential therapeutic agents. Marine peptides are a particularly interesting group of secondary metabolites because of their chemistry and wide range of biological activities. Among them, cyclic peptides exhibit a broad spectrum of antimicrobial activities, including against bacteria, protozoa, fungi, and viruses. Moreover, there are several examples of marine cyclic peptides revealing interesting antimicrobial activities against numerous drug-resistant bacteria and fungi, making these compounds a very promising resource in the search for novel antimicrobial agents to revert multidrug-resistance. This review summarizes 174 marine cyclic peptides with antibacterial, antifungal, antiparasitic, or antiviral properties. These natural products were categorized according to their sources—sponges, mollusks, crustaceans, crabs, marine bacteria, and fungi—and chemical structure—cyclic peptides and depsipeptides. The antimicrobial activities, including against drug-resistant microorganisms, unusual structural characteristics, and hits more advanced in (pre)clinical studies, are highlighted. Nocathiacins I–III (91–93), unnarmicins A (114) and C (115), sclerotides A (160) and B (161), and plitidepsin (174) can be highlighted considering not only their high antimicrobial potency in vitro, but also for their promising in vivo results. Marine cyclic peptides are also interesting models for molecular modifications and/or total synthesis to obtain more potent compounds, with improved properties and in higher quantity. Solid-phase Fmoc- and Boc-protection chemistry is the major synthetic strategy to obtain marine cyclic peptides with antimicrobial properties, and key examples are presented guiding microbiologist and medicinal chemists to the discovery of new antimicrobial drug candidates from marine sources.

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Section: Bacteria-produced Cyclic Peptidesmentioning

confidence: 96%

Marine Cyclic Peptides: Antimicrobial Activity and Synthetic Strategies

et al. 2022

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“…The X-ray structure of a complex of the N -terminal helical domain (NTD) of ClpC1 and Ruf I reveals distinct differences from the corresponding ClpC1-NTD-cyclomarin A structure. Surprisingly, the complex structure shows that the epoxide moiety of Ruf I is opened and covalently bound to ClpC1-NTD via the sulfur atom of a methionine in the binding pocket [ 92 , 93 ].…”

Section: Biological Activities and Mode Of Actionmentioning

confidence: 99%

Recent Developments on the Synthesis and Bioactivity of Ilamycins/Rufomycins and Cyclomarins, Marine Cyclopeptides That Demonstrate Anti-Malaria and Anti-Tuberculosis Activity

Kazmaier

Junk

2021

Marine Drugs

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Ilamycins/rufomycins and cyclomarins are marine cycloheptapeptides containing unusual amino acids. Produced by Streptomyces sp., these compounds show potent activity against a range of mycobacteria, including multidrug-resistant strains of Mycobacterium tuberculosis. The cyclomarins are also very potent inhibitors of Plasmodium falciparum. Biosynthetically the cyclopeptides are obtained via a heptamodular nonribosomal peptide synthetase (NRPS) that directly incorporates some of the nonproteinogenic amino acids. A wide range of derivatives can be obtained by fermentation, while bioengineering also allows the mutasynthesis of derivatives, especially cyclomarins. Other derivatives are accessible by semisynthesis or total syntheses, reported for both natural product classes. The anti-tuberculosis (anti-TB) activity results from the binding of the peptides to the N-terminal domain (NTD) of the bacterial protease-associated unfoldase ClpC1, causing cell death by the uncontrolled proteolytic activity of this enzyme. Diadenosine triphosphate hydrolase (PfAp3Aase) was found to be the active target of the cyclomarins in Plasmodia. SAR studies with natural and synthetic derivatives on ilamycins/rufomycins and cyclomarins indicate which parts of the molecules can be simplified or otherwise modified without losing activity for either target. This review examines all aspects of the research conducted in the syntheses of these interesting cyclopeptides.

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Structures of ClpC1-NTD with potent anti-TB cyclic peptides Rufomycin and Ecumicin: implications for the mechanism of action and design of therapeutic agents

Cited by 2 publications

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Marine Cyclic Peptides: Antimicrobial Activity and Synthetic Strategies

Marine Cyclic Peptides: Antimicrobial Activity and Synthetic Strategies

Recent Developments on the Synthesis and Bioactivity of Ilamycins/Rufomycins and Cyclomarins, Marine Cyclopeptides That Demonstrate Anti-Malaria and Anti-Tuberculosis Activity

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