A systematic analysis of all naturally-occurring glycosylated bacterial secondary metabolites reported in the scientific literature up through early 2013 is presented. This comprehensive analysis of 15 940 bacterial natural products revealed 3426 glycosides containing 344 distinct appended carbohydrates and highlights a range of unique opportunities for future biosynthetic study and glycodiversification efforts.

/pdf/a-comprehensive-review-of-glycosylated-bacterial-natural-4txxvyk4h3.pdf

A comprehensive review of glycosylated bacterial natural products.

Background: As multidrug-resistant (MDR) pathogens continue to emerge, there is a substantial amount of pressure to identify new drug candidates. Carboxyl polyethers, also referred to as polyether antibiotics, are a unique class of compounds with outstanding potency against a variety of critical infectious disease targets including protozoa, bacteria and viruses. The characteristics of these molecules that are of key interest are their selectivity and high potency against several MDR etiological agents. Objective: Although many studies have been published about carboxyl polyether antibiotics, there are no recent reviews of this class of drugs. The purpose of this review is to provide the reader with an overview of the spectrum of activity of polyether antibiotics, their mechanism of action, toxicity and potential as drug candidates to combat drug-resistant infectious diseases. Conclusion: Polyether ionophores show a high degree of promise for the potential control of drug-resistant bacterial and parasitic...

/pdf/polyether-ionophores-broad-spectrum-and-promising-4t8iv8cbdy.pdf

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

Polyether ionophores represent a large group of natural, biologically active substances produced by Streptomyces spp. They are lipid soluble and able to transport metal cations across cell membranes. Several of polyether ionophores are widely used as growth promoters in veterinary. Polyether antibiotics show a broad spectrum of bioactivity ranging from antibacterial, antifungal, antiparasitic, antiviral, and tumour cell cytotoxicity. Recently, it has been shown that some of these compounds are able to selectively kill cancer stem cells and multidrug-resistant cancer cells. Thus, they are recognized as new potential anticancer drugs. The biological activity of polyether ionophores is strictly connected with their molecular structure; therefore, the purpose of this paper is to present an overview of their formula, molecular structure, and properties.

/pdf/structures-and-properties-of-naturally-occurring-polyether-4wlbawjle1.pdf

Structures and properties of naturally occurring polyether antibiotics.

Monensin A (1a) from Streptomyces cinnamonensis is an antibiotic ionophore widely used in veterinary medicine and in animal husbandry (Scheme 1). It is one of the most important and best-studied members of a large family of structurally related polyketide secondary metabolites, the ionophoric polyethers, which are attracting renewed interest for their activity against drug-resistant strains of malaria. As with all natural polyethers, the molecule contains a multiplicity of asymmetric centers, but only one stereoisomer (out of a possible 2) is produced by S. cinnamonensis. The molecular basis for this exquisite stereocontrol is not known, and even the nature of the intermediates in polyether biosynthesis remains obscure. Early feeding studies established that monensin A (1a) is derived by a classic polyketide pathway from five acetate, one butyrate, and seven propionate units and that oxygen atoms at C1, C3, C5, C7, C9, and C25 arise from the carboxylate oxygen atoms of the corresponding carboxylic acid precursor units, whereas the remaining oxygen atoms at C13, C17, C21, and C26 are derived from molecular oxygen. On this basis, the “cascade” mechanism shown in Scheme 2a was proposed for the key oxidative steps. This mechanism involves the intermediacy of the linear E,E,E-triene 2 and of the triepoxide 3 as enzyme-free intermediates. However, it has proved difficult to obtain direct experimental support for this mechanism, and in particular, a synthetic sample of the full-length putative linear E,E,E-triene precursor 2 was found not to be incorporated into monensin A by S. cinnamonensis. The configuration of the double bonds in a putative linear precursor of monensin, as well as the mode of oxidative cyclization, therefore, remained undefined, and alternative pathways for oxidative cyclization that involved either a Z,Z,Z triene or a E,Z,Z triene have been subsequently proposed (Scheme 2b). The recent total sequencing of gene clusters for the biosynthesis of monensin and of nanchangmycin revealed, in each case, large open reading frames (ORFs) encoding a modular polyketide synthase (PKS) with the anticipated number of extension modules consistent with the production of a linear “pre-polyether” polyketide chain of the requisite length. Complete deletion of the gene cluster from S. cinnamonensis resulted in loss of monensin production, thus confirming its role in monensin biosynthesis. Each cluster contains numerous other genes, in particular four ORFs which, on the basis of database comparisons, appear to relate to the unusual oxidative cyclizations that are required to produce the polycyclic product. 7] Thus, the monensinproducing cluster contains an epoxidase gene (monCI), a gene with apparent similarity to an epoxide-opening enzyme (monCII), and two mutually homologous genes (monBI and monBII) with apparent similarity to the D-3-ketosteroid isomerase of Comamonas testosteroni and which were considered initially to possibly function as cis–trans isomerases. Further proof that MonCI was an epoxidase was obtained when a Streptomyces coelicolor strain that overexpressed monCI converted the unsaturated terpene (!)-linalool into linalool oxide at levels 10–20-fold higher than a control strain. Subsequently, it proved possible to interrupt polyketide-chain synthesis by genetically relocating a chain-terminating thioesterase (TE)/cyclase domain, obtained from the modular PKS that governs the biosynthesis of the macrolide erythromycin A in Saccharopolyspora erythraea, to downstream of extension module four of the monensin PKS. In the pentaketide released by this recombiScheme 1. The polyether ionophores monensin A (1a) and monensin B (1b). Oxygen atoms arising from molecular oxygen are denoted by *.

Accumulation of an E,E,E‐Triene by the Monensin‐Producing Polyketide Synthase when Oxidative Cyclization is Blocked

Sir: In the course of our screening program to discover antimalarial antibiotics from soil microorganisms which are active against drug-resistant parasites in vitro and in vivo, we previously reported that the polyether antibiotics X-206 and K-41 and other microbial metabolites exhibited potent antimalarial properties1-3). Thereafter, we found that a substance produced by an actinomycete strain OM-0060 had potent and selective antimalarial activities in vitro and in vivo. It was identified as borrelidin, a known nonglycosidic 18-membered macrolide antibiotic with a cyclopentanecarboxylic acid side chain (Fig. 1)4,5). We report here the antimalarial profile of borrelidin in comparison with those of clinically used antimalarial drugs. Borrelidin was isolated from the cultured broth of an actinomycete strain OM-0060. In vitro activities against Plasmodium falciparum strains K1 (drug-resistant) and FCR3 (drug-sensitive), and cytotoxicity against human diploid embryonic cell line MRC-5 were measured as described previously1). Rodent malaria-derived strains for in vivo 4-days suppressive testing, P. berghei N (drugsensitive) and P. yoelii ssp. NS (chloroquine-resistant) were used to assess in vivo antimalarial activities as described previously1,2). Test compounds were dissolved in 10% DMSO-Tween 80 aqueous solution and administered subcutaneously (s.c.) or orally (p.o.) to the mice two hours after infection with parasites (Day 0). Then the compounds were successively administered (s.c. or p.o.) to the infected mice once a day for 3 days (Days 1-3). On the day after the last treatment (Day 4), thin blood films were made from the tail blood of the mice, and the parasitaemia was determined as described previously2). Table 1 shows the in vitro antimalarial activities of borrelidin and the standard antimalarial drugs. Borrelidin showed more potent activity against the drug-resistant K1 strain of P. falciparum than the clinically used antimalarials, artemether, artesunate and chloroquine. Furthermore, borrelidin showed similar activity against the drug-sensitive FCR3 strain of P. falciparum to artemether and artesunate, and was more potent than chloroquine. The cytotoxicity of borrelidin against MRC-5 cells was relatively low (the IC50 value: 410nM). Borrelidin showed high selectivity indexes with the ratios of 216 and 228 for the MRC-5 cells/K1 strain and MRC-5 cells/FCR3 strain, respectively. Table 2 shows a preliminary comparison of the in vivo subcutaneous antimalarial activities of borrelidin and the standard antimalarial drugs. Borrelidin had antimalarial activity against both rodent malaria-derived P. berghei N and P. yoelii ssp. NS. Especially, borrelidin showed more potent subcutaneous antimalarial effects than artemether, artesunate and chloroquine against the chloroquine resistant strain (P. yoelii ssp. NS). The ED50 and ED90 values of borrelidin against P. yoelii ssp. NS were lower by factors 5.7-64 and 6.4->125, respectively, than those of the other three drugs. Borrelidin also showed more potent

In vitro and in vivo antimalarial activities of a non-glycosidic 18-membered macrolide antibiotic, borrelidin, against drug-resistant strains of Plasmodia.

In vitro and in vivo antimalarial activities of the monoglycoside polyether antibiotic, K-41 against drug resistant strains of Plasmodia.

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In vitro and in vivo antimalarial activities of the monoglycoside polyether antibiotic, K-41 against drug resistant strains of Plasmodia.