Iron chelators from mycobacteria (1954–1999) and potential therapeutic applications

Vergne, Anne; Walz, Andrew J.; Miller, Marvin J.

doi:10.1039/a809397k

Cited by 82 publications

(72 citation statements)

References 114 publications

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“…For that reason, we were interested in the biosynthesis gene of salicylic acid in Nocardia clinical isolates. Our preliminary PCR amplification studies using salicylic acid biosynthesis genes [12] indicated that most Nocardia species possess gene(s) for production of salicylic acid containing compounds. Although most such compounds are considered to belong to salicylic acid containing siderophores, there remains the strong possibility of finding novel bioactive secondary metabolites containing salicylic acid, similar to the transvalencin Z antibiotic studied here.…”

Section: Bioactive Assaymentioning

confidence: 99%

Transvalencin Z, a New Antimicrobial Compound with Salicylic Acid Residue from Nocardia transvalensis IFM 10065

et al. 2006

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Transvalencin Z was isolated from a culture broth of Nocardia transvalensis IFM 10065, a clinical isolate from a Japanese patient with actinomycotic mycetoma. The transvalencin Z structure was determined using NMR and mass spectrometric analyses. The structure is similar to a partial structure of siderophores such as mycobactins and nocobactins, but the compound has no cytotoxic activity. Transvalencin Z shows a strong antimicrobial activity against Gram-positive bacteria, but shows no activity against Gram-negative bacteria, fungi and tumor cells. Keywords transvalencin Z, siderophores, Nocardia transvalensis, nocobactin IntroductionMost Nocardia species can cause human infections called nocardiosis. The infections that are caused by Nocardia are considered rare, but infectious cases have been increasingly reported, especially with the increase of immunocompromised patients [1,2]. During our screening program of bioactive compounds from pathogenic actinomycetes, we found that most of the culture broth of Nocardia clinical isolates produce anti-tumor compounds that are extractable using hydrophobic solvents such as ethyl ether or n-hexane [3,4]. Our studies suggest that most of the active compounds from these pathogenic bacteria belong to siderophore-class antibiotics such as brasilibactin A [4], madurastatin [5] and asterobactin [6]. These siderophores are characterized as having salicylic acid moieties in their structures. We previously reported that N. transvalensis IFM 10065 produces a novel zinc-containing antibiotic, transvalencin A [6,7]. Our continuous screening of new bioactive metabolites from that bacterium has led to isolation of a novel antimicrobial compound with a salicylic acid moiety in its structure, designated as transvalencin Z (Fig. 1, 1). In this paper, we describe its production, isolation, physicochemical properties, structural characterization and biological activity.

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Section: Bioactive Assaymentioning

confidence: 99%

Transvalencin Z, a New Antimicrobial Compound with Salicylic Acid Residue from Nocardia transvalensis IFM 10065

et al. 2006

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“…Retrobiosynthesis of V. cholerae vibriobactin, N 1 -(2,3-dihydroxybenzoyl)-N 5 ,N 9 -bis[2-(2,3-dihydroxyphenyl)-5-methyloxazolinyl-4-carboxamido]norspermidine, shows that it is composed of three molecules of DHBA, two of L-threonine, and one of the unusual polyamine norspermidine [bis (3-aminopropyl)amine] (54,140,141). The 2-(2-hydroxyphenyl)-thiazolinyl-thiazolidine-4 carboxylate in yersiniabactin (41-43, 45, 55, 56, 83, 110, 114, 115) and pyochelin (87,93,94) is reminiscent of anguibactin, while the two 2-(2,3-dihydroxyphenyl)-5-methyl-oxazoline-4-carboxamide groups in vibriobactin (57,58) are reminiscent of the 2-(2-hydroxyphenyl)-oxazoline-4-carboxamide found in mycobactin from Mycobacterium tuberculosis (32,86,90,124,142,143).…”

Section: Introductionmentioning

confidence: 99%

“…Despite the availability of effective short-course chemotherapy (DOTS) and the Mycobacterium bovis Bacille CalmetteGuérin (BCG) vaccine, the tubercle bacillus continues to claim (90,124). Recent years have seen increased incidence of tuberculosis in both developing and industrialized countries, the widespread emergence of drug-resistant strains,and a deadly synergy with the human immunodeficiency virus.…”

Section: Mycobactin Introductionmentioning

confidence: 99%

Genetics and Assembly Line Enzymology of Siderophore Biosynthesis in Bacteria

Crosa

Walsh

2002

Microbiol Mol Biol Rev

719

697

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The regulatory logic of siderophore biosynthetic genes in bacteria involves the universal repressor Fur, which acts together with iron as a negative regulator. However in other bacteria, in addition to the Fur-mediated mechanism of regulation, there is a concurrent positive regulation of iron transport and siderophore biosynthetic genes that occurs under conditions of iron deprivation. Despite these regulatory differences the mechanisms of siderophore biosynthesis follow the same fundamental enzymatic logic, which involves a series of elongating acyl-S-enzyme intermediates on multimodular protein assembly lines: nonribosomal peptide synthetases (NRPS). A substantial variety of siderophore structures are produced from similar NRPS assembly lines, and variation can come in the choice of the phenolic acid selected as the N-cap, the tailoring of amino acid residues during chain elongation, the mode of chain termination, and the nature of the capturing nucleophile of the siderophore acyl chain being released. Of course the specific parts that get assembled in a given bacterium may reflect a combination of the inventory of biosynthetic and tailoring gene clusters available. This modular assembly logic can account for all known siderophores. The ability to mix and match domains within modules and to swap modules themselves is likely to be an ongoing process in combinatorial biosynthesis. NRPS evolution will try out new combinations of chain initiation, elongation and tailoring, and termination steps, possibly by genetic exchange with other microorganisms and/or within the same bacterium, to create new variants of iron-chelating siderophores that can fit a particular niche for the producer bacterium

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“…However, the exact role of metal ion coordination in the mechanism of action of UK-1 and analogs remains to be determined. There is a growing interest in the role of metal ions and their complexes in drug design [11][12][13][14], particularly in metal complex-DNA interactions [15][16][17][18][19][20][21]. Studies of UK-1 and its analogs may offer important insights, provided by nature, into how metal ion complexation can be harnessed in the design of selective cytotoxins.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, metal ion binding, and biological evaluation of new anticancer 2-(2′-hydroxyphenyl)benzoxazole analogs of UK-1

McKee¹,

Kerwin²

2008

Bioorganic & Medicinal Chemistry

160

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UK-1 is a bis(benzoxazole) natural product displaying activity against a wide range of human cancer cell lines. A simplified analog of UK-1, 4-carbomethoxy-2-(2'-hydroxyphenyl)benzoxazole, was previously found to be almost as active as UK-1 against cancer cell lines, and similar to the natural product, formed complexes with variety of metal ions such as Mg 2+ and Zn 2+ . A series 4-substituted-2-(2'-hydroxyphenyl)benzoxazole analogs of this "minimal pharmacophore" of UK-1 were prepared. The anti-cancer activity of these analogs was examined in breast and lung cancer cell lines. Spectrophotometric titrations in methanol were carried out in order to assess the ability of UK-1 and these analogs to coordinate with Mg 2+ and Cu 2+ ions. Although none of the new analogs were more cytotoxic than 4-carbomethoxy-2-(2'-hydroxyphenyl)benzoxazole, some analogs were identified that display similar cytotoxicity to this simplified UK-1 analog with improved water solubility. UK-1 and all of these new analogs bind Cu 2+ ions better than Mg 2+ ions, and the nature of the 4-substituent is important for the Mg 2+ ion binding ability of these 2-(2'-hydroxyphenyl) benzoxazoles. Previous studies of a limited number of UK-1 analogs demonstrated a correlation between Mg 2+ ion binding ability and cytotoxicity; however, within this series of 4-substituted-2-(2'-hydroxyphenyl)benzoxazoles the variations in cytotoxicity do not correlate with either Mg 2+ or Cu 2+ ion binding ability. These results, together with recent ESI-MS studies of Cu 2+ -mediated DNA binding by UK-1 and analogs, indicate that UK-1 and analogs may exert their cytotoxic effects by interaction with Cu 2+ or other transition metal ions, rather than Mg 2+ , and that metal ion-mediated DNA binding, rather than metal ion binding affinity, is important for the cytotoxic effect of these compounds. The potential role of Cu 2+ ions in the cytotoxic action of UK-1 is further supported by observation that UK-1 in the presence of Cu 2+ displays enhanced cytotoxicity to MCF-7 and A549 cells when compared to UK-1 alone.

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Iron chelators from mycobacteria (1954–1999) and potential therapeutic applications

Cited by 82 publications

References 114 publications

Transvalencin Z, a New Antimicrobial Compound with Salicylic Acid Residue from Nocardia transvalensis IFM 10065

Transvalencin Z, a New Antimicrobial Compound with Salicylic Acid Residue from Nocardia transvalensis IFM 10065

Genetics and Assembly Line Enzymology of Siderophore Biosynthesis in Bacteria

Synthesis, metal ion binding, and biological evaluation of new anticancer 2-(2′-hydroxyphenyl)benzoxazole analogs of UK-1

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