Mechanism of action of the copper(I) complex of 2,9-dimethyl-1,10-phenanthroline on Mycoplasma gallisepticum

Smit, Henk; Goot, H. van der; Nauta, W. Th.; Timmerman, Henk; Bolster, M W de; Stouthamer, A H; Vis, R.D.

doi:10.1128/aac.21.6.881

Cited by 20 publications

(14 citation statements)

References 11 publications

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“…First, we examined the antimicrobial activity of Neo against human mollicutes. Neo activity has previously been examined on a closely related avian mycoplasma, M. gallisepticum , and its antimicrobial activity was shown to be Cu-dependent (Smit et al, 1982; Gaisser et al, 1987a,b; de Zwart et al, 1991). The ureaplasma strains showed differential susceptibility to Neo in vitro (Table 2).…”

Section: Resultsmentioning

confidence: 99%

“…Previously published work with S. aureus and M. tuberculosis has demonstrated that compounds that chelate copper can exhibit antibacterial effects (Dalecki et al, 2016; Shah et al, 2016). Previous work in another laboratory during the 1980s examined the effect of Neo on Cu stress with M. gallisepticum (Smit et al, 1982; Gaisser et al, 1987b). The mechanism of action for Neo was determined to be the result of copper toxicity, and not that of the ligand itself (Smit et al, 1982).…”

Section: Discussionmentioning

confidence: 99%

“…Previous work in another laboratory during the 1980s examined the effect of Neo on Cu stress with M. gallisepticum (Smit et al, 1982; Gaisser et al, 1987b). The mechanism of action for Neo was determined to be the result of copper toxicity, and not that of the ligand itself (Smit et al, 1982). This was also found for DSF and its activity against M. tuberculosis where the drug was described as a Trojan horse, disguising copper during transition into the bacterial cell and thus preventing exclusion (Dalecki et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…Screening compounds for copper-dependent killing activity has resulted in the identification of new compounds with copper-dependent antimicrobial activity against Mycobacterium tuberculosis and Staphylococcus aureus (Dalecki et al, 2016; Shah et al, 2016). Previous work has been described examining the effect of antimicrobial compounds on copper-induced stress in Mycoplasma gallisepticum (Smit et al, 1982; Gaisser et al, 1987a,b; de Zwart et al, 1991), but to date studies in this area have not been conducted with human mycoplasmas or ureaplasmas. In the current study, we sought to determine whether compounds with Cu-binding activity exhibit antimicrobial activity against human mollicutes.…”

Section: Introductionmentioning

confidence: 99%

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Differential Susceptibility of Mycoplasma and Ureaplasma Species to Compound-Enhanced Copper Toxicity

et al. 2019

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Rationale Mycoplasmas represent important etiologic agents of many human diseases. Due to increasing antimicrobial resistance and slow rate of novel discovery, unconventional methods of drug discovery are necessary. Copper ions are utilized in host microbial killing, and bacteria must regulate intracellular Cu concentrations to avoid toxicity. We hypothesized that human mollicutes may have susceptibility to Cu-induced toxicity, and compounds that augment copper-dependent killing. Methods Mycoplasma pneumoniae (Mpn), Ureaplasma parvum (Up), Ureaplasma urealyticum (Uu), and Mycoplasma hominis (Mh) were exposed to CuSO 4 to determine minimal inhibitory concentrations (MICs). Once inhibitory concentrations had been determined, bacteria were treated with an FDA-approved drug disulfiram (DSF), glyoxal bis(4-methyl-3-thiosemicarbazone) (GTSM), and 2,9-dimethyl-1,10-phenanthroline (neocuproine), with or without Cu 2+ , to determine compound MICs. Results Ureaplasma species and Mh were able to tolerate 30–60 μM CuSO 4 , while Mpn tolerated over 10-fold higher concentrations (>1 mM). GTSM inhibited growth of all four organisms, but was unaffected by Cu 2+ addition. Inhibition by GTSM was reduced by addition of the cell-impermeant Cu chelator, bathocuproine disulfonate (BCS). Neocuproine exhibited Cu-dependent growth inhibition of all organisms. DSF exhibited Cu-dependent growth inhibition against Mh at low micromolar concentrations, and at intermediate concentrations for Mpn. Conclusion MICs for CuSO 4 differ widely among human mollicutes, with higher MICs for Mpn compared to Mh, Uu, and Up. DSF and Neocuproine exhibit Cu-dependent inhibition of mollicutes with copper concentrations between 25 and 50 μM. GTSM has copper-dependent anti-microbial activity at low levels of copper. Drug enhanced copper toxicity is a promising avenue for novel therapeutic development research with Mycoplasma and Ureaplasma species.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Differential Susceptibility of Mycoplasma and Ureaplasma Species to Compound-Enhanced Copper Toxicity

et al. 2019

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“…The antimycoplasmal activity of a series of bipyridyl analogues has been found to be de pendent on the transport of Cu+ ions across the mycoplasmal membrane by these com pounds [1][2][3]. The purpose of the present study was to investigate whether the composi tion of the membrane of different types of or ganisms would influence the inhibitory activ-…”

Section: Introductionmentioning

confidence: 99%

Influence of Membrane Composition of Various Parasites on the Inhibitory Activity of a Series of Bipyridyl Analogues

1994

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In a previous report the dependence of the antimycoplasmal activity of bipyridyl analogues on the presence of Cu⁺ ions has been shown. The inhibitory activity of these compounds has now been studied against Escherichia coli mycobacteria and Candida albicans in the absence and presence of Cu²⁺ ions using growth kinetic techniques. It was found that the inhibitory activity against E. coli increases in the presence of Cu²⁺ ions. In contrast, no additional effect of Cu²⁺ ions is observed for the inhibitory activity against mycobacteria. Some of the derivatives show very promising activity even against Mycobacterium avium strains. More complicated is the effect of Cu²⁺ ions on the inhibitory activity of the derivatives against C. albicans. For isoquinolones the observed delay in onset of inhibitors is reduced and no influence on the inhibitory activity is observed. The addition of Cu²⁺ ions to the phenanthrolines leads in contrast to a decrease in antifungal activity. The possible influence of membrane properties of the studied microorganism on the effect of Cu²⁺ ions is discussed.

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The chemistry of chelating agents in medical sciences

Bulman¹

1987

Coordination Compounds: Synthesis and Medical Application

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Mechanism of action of the copper(I) complex of 2,9-dimethyl-1,10-phenanthroline on Mycoplasma gallisepticum

Cited by 20 publications

References 11 publications

Differential Susceptibility of Mycoplasma and Ureaplasma Species to Compound-Enhanced Copper Toxicity

Differential Susceptibility of Mycoplasma and Ureaplasma Species to Compound-Enhanced Copper Toxicity

Influence of Membrane Composition of Various Parasites on the Inhibitory Activity of a Series of Bipyridyl Analogues

The chemistry of chelating agents in medical sciences

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