A new antimalarial polyether from a marine Streptomyces sp. H668

Abstract

The antimalarial guided fractionation of the culture of marine Streptomyces sp. strain H668 led to the isolation of a new polyether metabolite. The structure was determined by comprehensive NMR and MS assignments. This new metabolite showed in vitro antimalarial activity against both the chloroquine-susceptible (D6) and -resistant (W2) clones of Plasmodium falciparum, without cytotoxicity to normal cells (Vero) making it a promising first lead from this marine bacterium.Malaria is a tropical infection caused by four different species of protozoa from the genus Plasmodium transmitted to humans by the Anopheles mosquitoes. During past decades, chloroquine and other aminoquinolines have been utilized as frontline antimalarial agents. However, an increase in drug resistance in Plasmodium falciparum has made it essential to develop new chemotherapeutic agents in addition to combination therapies utilizing available antimalarial drugs with different modes of action. 1 Recently some specific polyether antibiotics have been reported to have potent antimalarial activity. 2-5 K-41, a carboxylic acid containing polyether antibiotic produced from Streptomyces hygroscopicus. K-41, has been reported to exhibit nanomolar in vitro antimalarial activity against Plasmodium falciparum strains K1 (drug resistant) and FCR3 (drug sensitive). 3 Furthermore, it showed high selectivity in vivo against both P. berghei strain N and P. yoelii strain NS infected mice, when administered orally. 3 Several polyethers from this class, such as lonomycin A, nigericin, and monensin have been identified as potential antimalarial agents due to their highly potent and selective activity. 4,5 These compounds classified as ionophores owe their potential activity to interact with ions (cations). A unique structural feature 4,5,11 is that they possess a polycyclic alkyl backbone which confers lipophilic character to these compounds and a terminal carboxyl group which plays an important role in the formation of oxygen rich internal cavity which is capable of binding metal ions. 11 Though rich in oxygen atoms, these molecules are lipophylic in nature. Since the parasite infected cell membrane is vulnerable to binding with lipophilic compounds, © 2008 Elsevier Ltd. All rights reserved. *Corresponding author. Tel.: +1-662-915-5730; fax: +1-662-915-5730; e-mail: mthamann@olemiss.edu. *Corresponding author. Tel.: +0-000-000-0000 ; fax: +0-000-000-0000 ; e-mail: hillr@umbi.umd.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. An antimalarial screening effort of marine microorganisms from Hawaiian sediments yie...

Polyether ionophores: broad-spectrum and promising biologically active molecules for the control of drug-resistant bacteria and parasites

“…A polyether isolated from the marine Streptomyces sp. H-668 and named hawaiimycin-I (34) ( Figure 1) [ 48 ] reinforced the critical role of certain key structural features including the terminal carboxylic group on the bioactivity of carboxyl ionophores. Hawaiimycin-I (34) is extremely close structurally to a set of carboxyl ionophores reported as potent antimalarial [ 40 ,44], that is, monensin A (1), K-41 (33), nigericin (5), lonomycin (17) and grisorixin (16).…”

Marine pharmacology in 2007–8: Marine compounds with antibacterial, anticoagulant, antifungal, anti-inflammatory, antimalarial, antiprotozoal, antituberculosis, and antiviral activities; affecting the immune and nervous system, and other miscellaneous mechanisms of action

“…CRIF1 isolated from a Thai soft coral, was moderately antiplasmodial (IC 50 =1-10 μM) against chloroquine-resistant P. falciparum strain 94. Na et al (2008) identified a new marine Streptomyces sp. H668 polyether (51) from Hawaii that showed in vitro antimalarial activity (IC 50 =0.1-0.2 μg/mL) against both P. falciparum chloroquine-susceptible (D6) and -resistant (W2) clones, with minimal cytotoxicity towards mammalian cells.…”

Marine Antimalarials

“…H668, exhibited a significant in vitro antimalarial activity (IC 50 ~ 150 ng/mL), with a good selectivity [84]. Some examples of non-marine antimalarial polyether compounds are also present in the literature [85].…”