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.
N1 - Funding Information:
This work was supported by National Institute of Health (grant numbers R01AI083125 and R01HL106786) to PK and also by Brazilian agencies Fundacao de Amparo à Pesquisa no Estado do Rio de Janeiro (FAPERJ) and Estado de São Paulo (FAPESP) (grant 2013/14957-5), Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES). PM would like to acknowledge the funding received through Dublin Institute of Technology's Arnold F. Graves Postdoctoral Fellowship scheme. Programa de Apoio ao Desenvolvimento Científico da Faculdade de Ciências Farmacêuticas da Unesp-PADC.
Publisher Copyright:
© 2018 McCarron, McCann, Devereux, Kavanagh, Skerry, Karakousis, Aor, Mello, Santos, Campos and Pavan.
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
UR - http://www.scopus.com/inward/record.url?scp=85049410050&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85049410050&partnerID=8YFLogxK
U2 - 10.3389/fmicb.2018.01432
DO - 10.3389/fmicb.2018.01432
M3 - Article
C2 - 30013535
AN - SCOPUS:85049410050
SN - 1664-302X
VL - 9
JO - Frontiers in Microbiology
JF - Frontiers in Microbiology
IS - JUL
M1 - 1432
ER -