Unprecedented in vitro antitubercular activitiy of manganese(II) complexes containing 1,10-phenanthroline and dicarboxylate ligands: Increased activity, superior selectivity, and lower toxicity in comparison to their copper(II) analogs

Pauraic McCarron; Malachy McCann; Michael Devereux; Kevin Kavanagh; Ciaran Skerry; Petros C. Karakousis; Ana C. Aor; Thaís P. Mello; André L.S. Santos; Débora L. Campos; Fernando R. Pavan

doi:10.3389/fmicb.2018.01432

Unprecedented in vitro antitubercular activitiy of manganese(II) complexes containing 1,10-phenanthroline and dicarboxylate ligands: Increased activity, superior selectivity, and lower toxicity in comparison to their copper(II) analogs

Pauraic McCarron, Malachy McCann, Michael Devereux, Kevin Kavanagh, Ciaran Skerry, Petros C. Karakousis, Ana C. Aor, Thaís P. Mello, André L.S. Santos, Débora L. Campos, Fernando R. Pavan

Research output: Contribution to journal › Article › peer-review

21 Citations (Scopus)

Abstract

Mycobacterium tuberculosis is the etiologic agent of tuberculosis. The demand for new chemotherapeutics with unique mechanisms of action to treat (multi)resistant strains is an urgent need. The objective of this work was to test the effect of manganese(II) and copper(II) phenanthroline/dicarboxylate complexes against M. tuberculosis. The water-soluble Mn(II) complexes, [Mn₂(oda)(phen)₄(H₂O)₂][Mn₂(oda)(phen)₄(oda)₂]·4H₂O (1) and ([Mn(3,6,9-tdda)(phen)₂]·3H₂O·EtOH)n (3) (odaH₂ = octanedioic acid, phen = 1,10-phenanthroline, tddaH₂ = 3,6,9-trioxaundecanedioic acid), and water-insoluble complexes, [Mn(ph)(phen)(H₂O)₂] (5), [Mn(ph)(phen)₂(H₂O)]·4H₂O (6), [Mn₂(isoph)₂(phen)₃]·4H₂O (7), ([Mn(phen)₂(H₂O)₂])₂(isoph)₂(phen)·12H₂O (8) and [Mn(tereph)(phen)₂]·5H₂O (9) (phH₂ = phthalic acid, isophH₂ = isophthalic acid, terephH₂ = terephthalic acid), robustly inhibited the viability of M. tuberculosis strains, H37Rv and CDC1551. The water-soluble Cu(II) analog of (1), [Cu₂(oda)(phen)₄](ClO₄)₂·2.76H₂O·EtOH (2), was significantly less effective against both strains. Whilst (3) retarded H37Rv growth much better than its soluble Cu(II) equivalent, ([Cu(3,6,9-tdda)(phen)₂]·3H₂O·EtOH)n (4), both were equally efficient against CDC1551. VERO and A549 mammalian cells were highly tolerant to the Mn(II) complexes, culminating in high selectivity index (SI) values. Significantly, in vivo studies using Galleria mellonella larvae indicated that the metal complexes were minimally toxic to the larvae. The Mn(II) complexes presented low MICs and high SI values (up to 1347), indicating their auspicious potential as novel antitubercular lead agents.

Original language	English
Article number	1432
Journal	Frontiers in Microbiology
Volume	9
Issue number	JUL
DOIs	https://doi.org/10.3389/fmicb.2018.01432
Publication status	Published - 2 Jul 2018

Keywords

1
10-phenanthroline
Antimicrobial agent
Galleria mellonella
Manganese(II)
Metal-based complex
Mycobacterium tuberculosis

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McCarron, P., McCann, M., Devereux, M., Kavanagh, K., Skerry, C., Karakousis, P. C., Aor, A. C., Mello, T. P., Santos, A. L. S., Campos, D. L., & Pavan, F. R. (2018). Unprecedented in vitro antitubercular activitiy of manganese(II) complexes containing 1,10-phenanthroline and dicarboxylate ligands: Increased activity, superior selectivity, and lower toxicity in comparison to their copper(II) analogs. Frontiers in Microbiology, 9(JUL), Article 1432. https://doi.org/10.3389/fmicb.2018.01432

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title = "Unprecedented in vitro antitubercular activitiy of manganese(II) complexes containing 1,10-phenanthroline and dicarboxylate ligands: Increased activity, superior selectivity, and lower toxicity in comparison to their copper(II) analogs",

abstract = "Mycobacterium tuberculosis is the etiologic agent of tuberculosis. The demand for new chemotherapeutics with unique mechanisms of action to treat (multi)resistant strains is an urgent need. The objective of this work was to test the effect of manganese(II) and copper(II) phenanthroline/dicarboxylate complexes against M. tuberculosis. The water-soluble Mn(II) complexes, [Mn2(oda)(phen)4(H2O)2][Mn2(oda)(phen)4(oda)2]·4H2O (1) and ([Mn(3,6,9-tdda)(phen)2]·3H2O·EtOH)n (3) (odaH2 = octanedioic acid, phen = 1,10-phenanthroline, tddaH2 = 3,6,9-trioxaundecanedioic acid), and water-insoluble complexes, [Mn(ph)(phen)(H2O)2] (5), [Mn(ph)(phen)2(H2O)]·4H2O (6), [Mn2(isoph)2(phen)3]·4H2O (7), ([Mn(phen)2(H2O)2])2(isoph)2(phen)·12H2O (8) and [Mn(tereph)(phen)2]·5H2O (9) (phH2 = phthalic acid, isophH2 = isophthalic acid, terephH2 = terephthalic acid), robustly inhibited the viability of M. tuberculosis strains, H37Rv and CDC1551. The water-soluble Cu(II) analog of (1), [Cu2(oda)(phen)4](ClO4)2·2.76H2O·EtOH (2), was significantly less effective against both strains. Whilst (3) retarded H37Rv growth much better than its soluble Cu(II) equivalent, ([Cu(3,6,9-tdda)(phen)2]·3H2O·EtOH)n (4), both were equally efficient against CDC1551. VERO and A549 mammalian cells were highly tolerant to the Mn(II) complexes, culminating in high selectivity index (SI) values. Significantly, in vivo studies using Galleria mellonella larvae indicated that the metal complexes were minimally toxic to the larvae. The Mn(II) complexes presented low MICs and high SI values (up to 1347), indicating their auspicious potential as novel antitubercular lead agents.",

keywords = "1, 10-phenanthroline, Antimicrobial agent, Galleria mellonella, Manganese(II), Metal-based complex, Mycobacterium tuberculosis",

author = "Pauraic McCarron and Malachy McCann and Michael Devereux and Kevin Kavanagh and Ciaran Skerry and Karakousis, {Petros C.} and Aor, {Ana C.} and Mello, {Tha{\'i}s P.} and Santos, {Andr{\'e} L.S.} and Campos, {D{\'e}bora L.} and Pavan, {Fernando R.}",

note = "Publisher Copyright: {\textcopyright} 2018 McCarron, McCann, Devereux, Kavanagh, Skerry, Karakousis, Aor, Mello, Santos, Campos and Pavan.",

year = "2018",

month = jul,

day = "2",

doi = "10.3389/fmicb.2018.01432",

language = "English",

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journal = "Frontiers in Microbiology",

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McCarron, P, McCann, M, Devereux, M, Kavanagh, K, Skerry, C, Karakousis, PC, Aor, AC, Mello, TP, Santos, ALS, Campos, DL & Pavan, FR 2018, 'Unprecedented in vitro antitubercular activitiy of manganese(II) complexes containing 1,10-phenanthroline and dicarboxylate ligands: Increased activity, superior selectivity, and lower toxicity in comparison to their copper(II) analogs', Frontiers in Microbiology, vol. 9, no. JUL, 1432. https://doi.org/10.3389/fmicb.2018.01432

Unprecedented in vitro antitubercular activitiy of manganese(II) complexes containing 1,10-phenanthroline and dicarboxylate ligands: Increased activity, superior selectivity, and lower toxicity in comparison to their copper(II) analogs. / McCarron, Pauraic; McCann, Malachy; Devereux, Michael et al.
In: Frontiers in Microbiology, Vol. 9, No. JUL, 1432, 02.07.2018.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Unprecedented in vitro antitubercular activitiy of manganese(II) complexes containing 1,10-phenanthroline and dicarboxylate ligands

T2 - Increased activity, superior selectivity, and lower toxicity in comparison to their copper(II) analogs

AU - McCarron, Pauraic

AU - McCann, Malachy

AU - Devereux, Michael

AU - Kavanagh, Kevin

AU - Skerry, Ciaran

AU - Karakousis, Petros C.

AU - Aor, Ana C.

AU - Mello, Thaís P.

AU - Santos, André L.S.

AU - Campos, Débora L.

AU - Pavan, Fernando R.

PY - 2018/7/2

Y1 - 2018/7/2

N2 - Mycobacterium tuberculosis is the etiologic agent of tuberculosis. The demand for new chemotherapeutics with unique mechanisms of action to treat (multi)resistant strains is an urgent need. The objective of this work was to test the effect of manganese(II) and copper(II) phenanthroline/dicarboxylate complexes against M. tuberculosis. The water-soluble Mn(II) complexes, [Mn2(oda)(phen)4(H2O)2][Mn2(oda)(phen)4(oda)2]·4H2O (1) and ([Mn(3,6,9-tdda)(phen)2]·3H2O·EtOH)n (3) (odaH2 = octanedioic acid, phen = 1,10-phenanthroline, tddaH2 = 3,6,9-trioxaundecanedioic acid), and water-insoluble complexes, [Mn(ph)(phen)(H2O)2] (5), [Mn(ph)(phen)2(H2O)]·4H2O (6), [Mn2(isoph)2(phen)3]·4H2O (7), ([Mn(phen)2(H2O)2])2(isoph)2(phen)·12H2O (8) and [Mn(tereph)(phen)2]·5H2O (9) (phH2 = phthalic acid, isophH2 = isophthalic acid, terephH2 = terephthalic acid), robustly inhibited the viability of M. tuberculosis strains, H37Rv and CDC1551. The water-soluble Cu(II) analog of (1), [Cu2(oda)(phen)4](ClO4)2·2.76H2O·EtOH (2), was significantly less effective against both strains. Whilst (3) retarded H37Rv growth much better than its soluble Cu(II) equivalent, ([Cu(3,6,9-tdda)(phen)2]·3H2O·EtOH)n (4), both were equally efficient against CDC1551. VERO and A549 mammalian cells were highly tolerant to the Mn(II) complexes, culminating in high selectivity index (SI) values. Significantly, in vivo studies using Galleria mellonella larvae indicated that the metal complexes were minimally toxic to the larvae. The Mn(II) complexes presented low MICs and high SI values (up to 1347), indicating their auspicious potential as novel antitubercular lead agents.

AB - Mycobacterium tuberculosis is the etiologic agent of tuberculosis. The demand for new chemotherapeutics with unique mechanisms of action to treat (multi)resistant strains is an urgent need. The objective of this work was to test the effect of manganese(II) and copper(II) phenanthroline/dicarboxylate complexes against M. tuberculosis. The water-soluble Mn(II) complexes, [Mn2(oda)(phen)4(H2O)2][Mn2(oda)(phen)4(oda)2]·4H2O (1) and ([Mn(3,6,9-tdda)(phen)2]·3H2O·EtOH)n (3) (odaH2 = octanedioic acid, phen = 1,10-phenanthroline, tddaH2 = 3,6,9-trioxaundecanedioic acid), and water-insoluble complexes, [Mn(ph)(phen)(H2O)2] (5), [Mn(ph)(phen)2(H2O)]·4H2O (6), [Mn2(isoph)2(phen)3]·4H2O (7), ([Mn(phen)2(H2O)2])2(isoph)2(phen)·12H2O (8) and [Mn(tereph)(phen)2]·5H2O (9) (phH2 = phthalic acid, isophH2 = isophthalic acid, terephH2 = terephthalic acid), robustly inhibited the viability of M. tuberculosis strains, H37Rv and CDC1551. The water-soluble Cu(II) analog of (1), [Cu2(oda)(phen)4](ClO4)2·2.76H2O·EtOH (2), was significantly less effective against both strains. Whilst (3) retarded H37Rv growth much better than its soluble Cu(II) equivalent, ([Cu(3,6,9-tdda)(phen)2]·3H2O·EtOH)n (4), both were equally efficient against CDC1551. VERO and A549 mammalian cells were highly tolerant to the Mn(II) complexes, culminating in high selectivity index (SI) values. Significantly, in vivo studies using Galleria mellonella larvae indicated that the metal complexes were minimally toxic to the larvae. The Mn(II) complexes presented low MICs and high SI values (up to 1347), indicating their auspicious potential as novel antitubercular lead agents.

KW - 1

KW - 10-phenanthroline

KW - Antimicrobial agent

KW - Galleria mellonella

KW - Manganese(II)

KW - Metal-based complex

KW - Mycobacterium tuberculosis

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U2 - 10.3389/fmicb.2018.01432

DO - 10.3389/fmicb.2018.01432

M3 - Article

SN - 1664-302X

VL - 9

JO - Frontiers in Microbiology

JF - Frontiers in Microbiology

IS - JUL

M1 - 1432

ER -

McCarron P, McCann M, Devereux M, Kavanagh K, Skerry C, Karakousis PC et al. Unprecedented in vitro antitubercular activitiy of manganese(II) complexes containing 1,10-phenanthroline and dicarboxylate ligands: Increased activity, superior selectivity, and lower toxicity in comparison to their copper(II) analogs. Frontiers in Microbiology. 2018 Jul 2;9(JUL):1432. doi: 10.3389/fmicb.2018.01432