Antimycobacterial activity of rhodamine 3,4-HPO iron chelators against Mycobacterium avium: analysis of the contribution of functional groups and of chelator's combination with ethambutol

Moniz, Tânia; Silva, Daniel; Silva, Tânia; Gomes, Maria Salomé; Rangel, Maria

doi:10.1039/c5md00456j

Cited by 22 publications

(25 citation statements)

References 52 publications

(66 reference statements)

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“…In the clinics, ethambutol is used in combination with other antimycobacterial drugs, not only as a strategy to prevent the appearance of resistant strains but also due to its high toxicity when given alone in high doses ( 9 , 41 ). The advantageous combination of ethambutol and iron chelators in the control of M. avium growth inside macrophages was recently reported ( 45 ). Ethambutol acts by impairing the biosynthesis of the cell wall, increasing cell permeability, and potentiating the actions of other drugs ( 9 , 46 , 47 ).…”

Section: Discussionmentioning

confidence: 99%

Lactoferricin Peptides Increase Macrophages' Capacity To Kill Mycobacterium avium

Silva

Moreira

Nazmi

et al. 2017

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The genus Mycobacterium comprises several pathogenic species, including M. tuberculosis, M. leprae, M. avium, etc. Infections caused by these bacteria are particularly difficult to treat due to their intrinsic impermeability, low growth rate, and intracellular localization. Antimicrobial peptides are increasingly acknowledged as potential treatment tools, as they have a high spectrum of activity, low tendency to induce bacterial resistance, and immunomodulatory properties. In this study, we show that peptides derived from bovine lactoferricin (LFcin) improve the antimicrobial activity of ethambutol against Mycobacterium avium growing inside macrophages. Moreover, the d-enantiomer of a short version of lactoferricin containing amino acids 17 to 30 (d-LFcin17–30) causes intramacrophagic death of M. avium by increasing the formation of lysosomes and autophagosomes. This work opens the way to the use of lactoferricin-derived peptides to treat infections caused by mycobacteria and highlights important modulatory effects of d-FLcin17–30 on macrophages, which may be useful under other conditions in which macrophage activation is needed.

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Section: Discussionmentioning

confidence: 99%

Lactoferricin Peptides Increase Macrophages' Capacity To Kill Mycobacterium avium

Silva

Moreira

Nazmi

et al. 2017

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“…To achieve that purpose we synthesized the set of compounds in Figure 6 and tested their activity against M. avium in comparison with that of the lead chelator MRH7 [109]. The results showed that all the fluorescent chelators exhibit antimycobacterial effect and corroborated the relevance of the thiourea linkage, the ethyl substituents on the amino groups of the xanthene ring and the advantage of their associated inclusion in the molecular framework.…”

Section: Design Of 3-hydroxy-4-pyridinone Chelators To Address Mycmentioning

confidence: 97%

“…Considering the molecular structure of mycobacterial siderophores and bearing in mind that in order to compete for Fe different chelating units, that originate chelators with higher affinity for Fe(III) are necessary, we selected ligands of the 3-hydroxy-4-pyridinone class to achieve our purpose. This class of chelators and their complexes have proved to be useful in several fields of application [95,108,109,110,111]. In what concerns biomedical applications [112,113], Deferiprone (1,2-dimethyl-3-hydroxy-4-pyridinone) is one of the ligands in clinical use to treat iron overload in thalassemia major patients [114,115,116,117].…”

Section: Design Of 3-hydroxy-4-pyridinone Chelators To Address Mycmentioning

confidence: 99%

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Tuning the Anti(myco)bacterial Activity of 3-Hydroxy-4-pyridinone Chelators through Fluorophores

et al. 2018

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Controlling the sources of Fe available to pathogens is one of the possible strategies that can be successfully used by novel antibacterial drugs. We focused our interest on the design of chelators to address Mycobacterium avium infections. Taking into account the molecular structure of mycobacterial siderophores and considering that new chelators must be able to compete for Fe(III), we selected ligands of the 3-hydroxy-4-pyridinone class to achieve our purpose. After choosing the type of chelating unit it was also our objective to design chelators that could be monitored inside the cell and for that reason we designed chelators that could be functionalized with fluorophores. We didn’t realize at the time that the incorporation a fluorophore, to allow spectroscopic detection, would be so relevant for the antimycobacterial effect or to determine the affinity of the chelators towards biological membranes. From a biophysical perspective, this is a fascinating illustration of the fact that functionalization of a molecule with a particular label may lead to a change in its membrane permeation properties and result in a dramatic change in biological activity. For that reason we believe it is interesting to give a critical account of our entire work in this area and justify the statement “to label means to change”. New perspectives regarding combined therapeutic approaches and the use of rhodamine B conjugates to target closely related problems such as bacterial resistance and biofilm production are also discussed.

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“…Furthermore, we have developed new molecules based on the 3-hydroxy-4-pyridinone iron-chelating moiety, in which the inclusion of a rhodamine residue improved antimycobacterial activity, presumably through improved intracellular distribution and targeting for the mycobacteria-containing phagosome [201,202]. Interestingly, these iron chelators had synergistic activity with ethambutol in decreasing M. avium growth inside macrophages [203]. Curiously, in a study aimed at the characterization of the antimicrobial effect of ATP, the authors claimed that ATP inhibits the growth of MAC through iron chelation [204].…”

Section: Iron Chelatorsmentioning

confidence: 99%

Looking beyond Typical Treatments for Atypical Mycobacteria

2020

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The genus Mycobacterium comprises not only the deadliest of bacterial pathogens, Mycobacterium tuberculosis, but several other pathogenic species, including M. avium and M. abscessus. The incidence of infections caused by atypical or nontuberculous mycobacteria (NTM) has been steadily increasing, and is associated with a panoply of diseases, including pulmonary, soft-tissue, or disseminated infections. The treatment for NTM disease is particularly challenging, due to its long duration, to variability in bacterial susceptibility profiles, and to the lack of evidence-based guidelines. Treatment usually consists of a combination of at least three drugs taken from months to years, often leading to severe secondary effects and a high chance of relapse. Therefore, new treatment approaches are clearly needed. In this review, we identify the main limitations of current treatments and discuss different alternatives that have been put forward in recent years, with an emphasis on less conventional therapeutics, such as antimicrobial peptides, bacteriophages, iron chelators, or host-directed therapies. We also review new forms of the use of old drugs, including the repurposing of non-antibacterial molecules and the incorporation of antimicrobials into ionic liquids. We aim to stimulate advancements in testing these therapies in relevant models, in order to provide clinicians and patients with useful new tools with which to treat these devastating diseases.

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Antimycobacterial activity of rhodamine 3,4-HPO iron chelators against Mycobacterium avium: analysis of the contribution of functional groups and of chelator's combination with ethambutol

Abstract: ChelatorMRH7(thiourea linkage; ethyl substituents) and its co-administration with ethambutol are the best choices for a higher antimycobacterial effect.

Cited by 22 publications

References 52 publications

Lactoferricin Peptides Increase Macrophages' Capacity To Kill Mycobacterium avium

Lactoferricin Peptides Increase Macrophages' Capacity To Kill Mycobacterium avium

Tuning the Anti(myco)bacterial Activity of 3-Hydroxy-4-pyridinone Chelators through Fluorophores

Looking beyond Typical Treatments for Atypical Mycobacteria

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