Development of metal-chelating inhibitors for the Class II fructose 1,6-bisphosphate (FBP) aldolase

Labbé, Geneviève; Krismanich, Anthony P.; Groot, Sarah de; Rasmusson, Timothy; Shang, Muhong; Brown, Matthew D.R.; Dmitrienko, Gary I.; Guillemette, J. Guy

doi:10.1016/j.jinorgbio.2012.02.032

Cited by 25 publications

(35 citation statements)

References 39 publications

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“…S1D in the supplemental material). HCA was previously reported to inhibit the zinc-dependent fructose 1,6-bisphosphate aldolase of M. tuberculosis in enzymatic assays (9,46). In accordance with previous reports (9), we confirmed that the compound is a relatively poor inhibitor of whole cells (see Fig.…”

Section: Resultssupporting

confidence: 93%

“…The only existing experimental evidence for a metal-related mode of action for this type of compound against M. tuberculosis therefore probably comes from in vitro enzymatic screens on mycobacterial metalloenzymes. The most recent targets were the two methionine aminopeptidases metA (rv0734) and metB (rv2861c) and fructose 1,6-bisphosphate aldolase (fba, rv0363c) (9,46,58). These enzymes are inhibited by the 8HQ derivative HCA through documented interactions between the inhibitor and a catalytically essential zinc or cobalt ion (9,46,58).…”

Section: Discussionmentioning

confidence: 99%

“…The most recent targets were the two methionine aminopeptidases metA (rv0734) and metB (rv2861c) and fructose 1,6-bisphosphate aldolase (fba, rv0363c) (9,46,58). These enzymes are inhibited by the 8HQ derivative HCA through documented interactions between the inhibitor and a catalytically essential zinc or cobalt ion (9,46,58). However, an often observed shortcoming of enzymatic inhibitors from such target-based approaches is the lack of significant activity on respective model organisms (59), and unfortunately, HCA is no exception (9).…”

Section: Discussionmentioning

confidence: 99%

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8-Hydroxyquinolines Are Boosting Agents of Copper-Related Toxicity in Mycobacterium tuberculosis

Shah

Dalecki

Malalasekera

et al. 2016

Antimicrob Agents Chemother

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c Copper (Cu) ions are likely the most important immunological metal-related toxin utilized in controlling bacterial infections. Impairment of bacterial Cu resistance reduces viability within the host. Thus, pharmacological enhancement of Cu-mediated antibacterial toxicity may lead to novel strategies in drug discovery and development. Screening for Cu toxicity-enhancing antibacterial molecules identified 8-hydroxyquinoline (8HQ) to be a potent Cu-dependent bactericidal inhibitor of Mycobacterium tuberculosis. The MIC of 8HQ in the presence of Cu was 0.16 M for replicating and nonreplicating M. tuberculosis cells. We found 8HQ's activity to be dependent on the presence of extracellular Cu and to be related to an increase in cell-associated labile Cu ions. Both findings are consistent with 8HQ acting as a Cu ionophore. Accordingly, we identified the 1:1 complex of 8HQ and Cu to be its active form, with Zn, Fe, or Mn neither enhancing nor reducing its Cu-specific action. This is remarkable, considering that the respective metal complexes have nearly identical structures and geometries. Finally, we found 8HQ to kill M. tuberculosis selectively within infected primary macrophages. Given the stark Cu-dependent nature of 8HQ activity, this is the first piece of evidence that Cu ions within macrophages may bestow antibacterial properties to a Cu-dependent inhibitor of M. tuberculosis. In conclusion, our findings highlight the metal-binding ability of the 8-hydroxyquinoline scaffold to be a potential focus for future medicinal chemistry and highlight the potential of innate immunity-inspired screening platforms to reveal molecules with novel modes of action against M. tuberculosis.

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Section: Resultssupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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8-Hydroxyquinolines Are Boosting Agents of Copper-Related Toxicity in Mycobacterium tuberculosis

Shah

Dalecki

Malalasekera

et al. 2016

Antimicrob Agents Chemother

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“…6–9,12–14,38 Although previous class II FBA inhibitor development efforts have been able to deliver potent substrate-based analogs selective for class II over class I FBAs, the recurring theme throughout studies utilizing class II FBA substrates as a scaffold is the necessity of these inhibitors to possess highly charged phosphate groups. 8,13,38 As phosphorylation of glycolytic intermediates is a method for cells to retain these intermediates within the cytosol, their inclusion into class II FBA inhibitors has been problematic.…”

Section: Discussionmentioning

confidence: 99%

A Noncompetitive Inhibitor forMycobacterium tuberculosis’s Class IIa Fructose 1,6-Bisphosphate Aldolase

et al. 2013

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Class II fructose 1,6-bisphosphate aldolase (FBA) is an enzyme critical for bacterial, fungal, and protozoan glycolysis/gluconeogenesis. Importantly, humans lack this type of aldolase, having instead a class I FBA that is structurally and mechanistically distinct from class II FBAs. As such, class II FBA is considered a putative pharmacological target for the development of novel antibiotics against pathogenic bacteria such as Mycobacterium tuberculosis, the causative agent for tuberculosis (TB). To date, several competitive class II FBA substrate mimic-styled inhibitors have been developed; however, they lack either specificity, potency, or properties that limit their potential as possible therapeutics. Recently, through the use of enzymatic and structure-based assisted screening, we identified 8-hydroxyquinoline carboxylic acid (HCA) that has an IC50 of 10 ± 1 μM for the class II FBA present in M. tuberculosis (MtFBA). As opposed to previous inhibitors, HCA behaves in a noncompetitive manner, shows no inhibitory properties toward human and rabbit class I FBAs, and possesses anti-TB properties. Furthermore, we were able to determine the crystal structure of HCA bound to MtFBA to 2.1 Å. HCA also demonstrates inhibitory effects for other class II FBAs, including pathogenic bacteria such as methicillin-resistant Staphylococcus aureus. With its broad-spectrum potential, unique inhibitory characteristics, and flexibility of functionalization, the HCA scaffold likely represents an important advancement in the development of class II FBA inhibitors that can serve as viable preclinical candidates.

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“…glycolysis, gluconeogenesis, pentose phosphate pathway, fructose and mannose metabolism. Molecular modeling of the derivatives in the enzymes' active site was also used to design a new generation of inhibitors [33].…”

Section: Resultsmentioning

confidence: 99%

Mining the Proteome of Haemophilus ducreyi for Identification of Potential Drug Targets

Sarangi¹,

Gupta²,

Trivedi³

et al. 2010

TOBIOIJ

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Abstract:Chancroid is an extremely infectious sexually transmitted disease (STD) caused by the bacterium Haemophilus ducreyi, prevalent in Africa, United States and in some parts of South Asia. Chancroid has been recognized as a cofactor for human immunodeficiency virus (HIV) transmission. So, there is a requirement to develop an efficient drug to combat chancroid, which can also diminish the HIV prevalence in those populations where chancroid is a prime source for HIV infection. The availability of the complete proteome information of H. ducreyi help enabled in silico analysis for identification of potential vaccine candidates and drug targets. Our study revealed 1226 proteins in H. ducreyi to be nonhomologous with human proteome. Screening these proteins using the Database of Essential Genes (DEG) resulted in the identification of 451 essential proteins. Analysis of the identified essential proteins, using the KEGG Automated Annotation Server (KAAS), revealed 40 proteins of H. ducreyi as potential drug targets as they are involved in pathogen specific metabolic pathways. Subcellular localization prediction of these 451 essential proteins revealed that 11 proteins lie on the outer membrane of the pathogen which could be potential vaccine candidates. Functional family prediction for the 50 putative uncharacterized essential proteins of H. ducreyi by SVM-Prot web server revealed that out of 50, 3 proteins as transmembrane proteins, which may be potential drug targets. Identification of potential inhibitors against these targets through virtual screening may consequence in detection of novel lead compounds effective against H. ducreyi to combat chancroid.

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Development of metal-chelating inhibitors for the Class II fructose 1,6-bisphosphate (FBP) aldolase

Cited by 25 publications

References 39 publications

8-Hydroxyquinolines Are Boosting Agents of Copper-Related Toxicity in Mycobacterium tuberculosis

8-Hydroxyquinolines Are Boosting Agents of Copper-Related Toxicity in Mycobacterium tuberculosis

A Noncompetitive Inhibitor forMycobacterium tuberculosis’s Class IIa Fructose 1,6-Bisphosphate Aldolase

Mining the Proteome of Haemophilus ducreyi for Identification of Potential Drug Targets

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