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

Abstract

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.

Marine Cyclic Peptides: Antimicrobial Activity and Synthetic Strategies

“…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].…”

“…Rufomycin A (102) and rufomycin B (103) have been reported to be highly active against Mycobacterium smegmatis, at 0.2 µg/mL and 0.5 µg/mL, respectively, and M. tuberculosis, at 0.1-0.4 µg/mL and 1-5 µg/mL, respectively, and also against strains resistant to other antibiotics (kanamycin, streptomycin, neomycin, and isonicotinic acid hydrazide). In addition, no significant toxicity was observed on four-week-old mice with intraperitoneal injection of 102 (LD 0 200 mg/kg and LD 100 360 mg/kg) [192]. In another study, rufomycin NBZ8 (104) was found to be the most active peptide, with an MIC of 0.02 µM (M. tuber.…”

“…Rufomycins A (102) and B (103), also known as ilamycins [191], are highly interesting marine cyclopeptides [192], isolated from marine Streptomyces sp. [192][193][194][195][196][197][198].…”

“…Rufomycins A (102) and B (103), also known as ilamycins [191], are highly interesting marine cyclopeptides [192], isolated from marine Streptomyces sp. [192][193][194][195][196][197][198]. Related peptides are characterized by their unusual amino acids and potent activity against a range of mycobacteria, including multidrug-resistant strains of Mycobacterium tuberculosis.…”

Synthesis of Marine Natural Products and Molecules Inspired by Marine Substances II

“…In a review by Kazmaier and Junk [ 3 ], cycloheptapeptides molecules as ilamycins, rufomycins, and cyclomarins, including unusual amino acids with important biological activities, are treated. These substances are specifically active against a range of mycobacteria with no significant activity towards other Gram-positive and Gram-negative bacteria or fungi.…”