Identification of a new hexadentate iron chelator capable of restricting the intramacrophagic growth of Mycobacterium avium

Fernandes, Sofia; Nunes, Ana; Gomes, Ana; Castro, Balt­azar de; Hider, Robert C.; Rangel, Maria; Appelberg, Rui; Gomes, Maria Salomé

doi:10.1016/j.micinf.2010.01.003

Cited by 43 publications

(53 citation statements)

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“…Chelators are able to restrict growth of Mycobacterium avium (46)(47)(48), while synthetic mycobactin analogues selectively inhibit M. tuberculosis growth (49). Additionally, iron chelation has proved to inhibit the cytotoxic effect of mycolactone, a macrolide toxin produced by Mycobacterium ulcerans, the causative agent of the necrotizing skin disease Buruli ulcer (50).…”

Section: Discussionmentioning

confidence: 99%

A Novel Antimycobacterial Compound Acts as an Intracellular Iron Chelator

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Poce

Alfonso

et al. 2015

Antimicrob Agents Chemother

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Efficient iron acquisition is crucial for the pathogenesis of Mycobacterium tuberculosis. Mycobacterial iron uptake and metabolism are therefore attractive targets for antitubercular drug development. Resistance mutations against a novel pyrazolopyrimidinone compound (PZP) that is active against M. tuberculosis have been identified within the gene cluster encoding the ESX-3 type VII secretion system. ESX-3 is required for mycobacterial iron acquisition through the mycobactin siderophore pathway, which could indicate that PZP restricts mycobacterial growth by targeting ESX-3 and thus iron uptake. Surprisingly, we show that ESX-3 is not the cellular target of the compound. We demonstrate that PZP indeed targets iron metabolism; however, we found that instead of inhibiting uptake of iron, PZP acts as an iron chelator, and we present evidence that the compound restricts mycobacterial growth by chelating intrabacterial iron. Thus, we have unraveled the unexpected mechanism of a novel antimycobacterial compound.

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Section: Discussionmentioning

confidence: 99%

A Novel Antimycobacterial Compound Acts as an Intracellular Iron Chelator

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Poce

Alfonso

et al. 2015

Antimicrob Agents Chemother

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“…Conversely, several host factors exist whose role is to restrict iron and form a nutritional barrier (reviewed in reference 9). Pathogen iron acquisition could be further disrupted by using biologically compatible chelators (6)(7)(8) or by introducing gallium as a competitor (1).…”

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confidence: 99%

In Vitro and In Vivo Biological Activities of Iron Chelators and Gallium Nitrate against Acinetobacter baumannii

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Harris

KuoLee

et al. 2012

Antimicrob Agents Chemother

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We investigated the ability of compounds interfering with iron metabolism to inhibit the growth of Acinetobacter baumannii. Iron restriction with transferrin or 2,2-bipyridyl significantly inhibited A. baumannii growth in vitro. Gallium nitrate alone was moderately effective at reducing A. baumannii growth but became bacteriostatic in the presence of serum or transferrin. More importantly, gallium nitrate treatment reduced lung bacterial burdens in mice. The use of gallium-based therapies shows promise for the control of multidrug-resistant A. baumannii. Acinetobacter baumannii has emerged as a major cause of both community-associated and nosocomial infections worldwide. Infections have become increasingly difficult to treat because of the rapid development of A. baumannii antibiotic resistance. Counteracting the action of virulence factors represents a novel strategy of infection control with potentially high specificity and low impact on the host. Hence, identification of the critical factors necessary for the in vivo success of the pathogen might reveal novel therapeutic targets.One characteristic shared by virulent bacteria is their ability to acquire iron in the blood and tissues, where its availability is low. Conversely, several host factors exist whose role is to restrict iron and form a nutritional barrier (reviewed in reference 9). Pathogen iron acquisition could be further disrupted by using biologically compatible chelators (6-8) or by introducing gallium as a competitor (1).To examine the biological activity of iron-restricting compounds against A. baumannii, we first investigated the effect of a selection of iron chelators on A. baumannii ATCC 17978 growth in different media. 2,2-Bipyridyl (BiP) is a classical iron chelator and was chosen as a positive control for both metal depletion and growth inhibition of many organisms. Pyridoxal isonicotinyl hydrazone (PIH) is a potent cell-permeable chela-

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“…Both classes of ligands and respective complexes have been extensively studied due to their broad field of application namely in therapeutics and diagnosis, solvent extraction and chemical analysis. [1][2][3][4][5][6] 3-Hydroxy-4-pyridinones are heterocyclic compounds that include a nitrogen atom in the ring and hydroxylic and ketonic oxygen atoms in positions 3 and 4, respectively (Figure 1) which confer the strong chelating properties exhibited by the ligands towards M II /M III metal ions. The ligands are synthetically versatile allowing the introduction of different substituents in several positions of the heterocyclic ring without producing a significant change in complexation ability and acid-base properties.…”

Section: Introductionmentioning

confidence: 99%

“…The values of the stability constants are consistent with the Irving-Williams series and indicate the formation of stable ML 2 complexes which were isolated and characterized. Following the trend observed for 3-hydroxy-4-pyridinone ligands the solids were obtained as hydrates whose composition was characterized as [ML 2 (H 2 O) 2 ]·xH 2 O complexes. DFT calculations allowed geometry optimization and provided information about bond lengths and angles.…”

Section: Introductionmentioning

confidence: 99%

Nickel(II) and Cobalt(II) 3‐Hydroxy‐4‐pyridinone Complexes: Synthesis, Characterization and Speciation Studies in Aqueous Solution

et al. 2010

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The interaction of nickel(II) and cobalt(II) with a set of 3‐hydroxy‐4‐pyridinone ligands (Hmpp, Hmepp, Hetpp, Hempp, Hdepp and Hdmpp) was investigated in aqueous solution. The family of chelators under study is pharmaceutically relevant in the treatment of iron‐overloaded patients and it is foreseen to be of use in occupational health situations associated with accumulation of nickel and cobalt such as nasal/pulmonary and skin hazards and allergies. Ligand dissociation constants and stability constants for the cobalt(II) and nickel(II) complexes have been determined by potentiometric methods allowing the establishment of the corresponding speciation plots as a function of pH. The values of the stability constants are consistent with the Irving–Williams series and indicate the formation of stable ML2 complexes which were isolated and characterized. Following the trend observed for 3‐hydroxy‐4‐pyridinone ligands the solids were obtained as hydrates whose composition was characterized as [ML2(H2O)2]·xH2O complexes. DFT calculations allowed geometry optimization and provided information about bond lengths and angles.

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Identification of a new hexadentate iron chelator capable of restricting the intramacrophagic growth of Mycobacterium avium

Cited by 43 publications

References 20 publications

A Novel Antimycobacterial Compound Acts as an Intracellular Iron Chelator

A Novel Antimycobacterial Compound Acts as an Intracellular Iron Chelator

In Vitro and In Vivo Biological Activities of Iron Chelators and Gallium Nitrate against Acinetobacter baumannii

Nickel(II) and Cobalt(II) 3‐Hydroxy‐4‐pyridinone Complexes: Synthesis, Characterization and Speciation Studies in Aqueous Solution

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