Is IQG-607 a Potential Metallodrug or Metallopro-Drug With a Defined Molecular Target in Mycobacterium tuberculosis?

Abstract

The emergence of strains of Mycobacterium tuberculosis resistant to isoniazid (INH) has underscored the need for the development of new anti-tuberculosis agents. INH is activated by the mycobacterial katG-encoded catalase-peroxidase, forming an acylpyridine fragment that is covalently attached to the C4 of NADH. This isonicotinyl-NAD adduct inhibits the activity of 2-trans-enoyl-ACP(CoA) reductase (InhA), which plays a role in mycolic acid biosynthesis. A metal-based INH analog, Na3[FeII(CN)5(INH)]·4H2O, IQG-607, was designed to have an electronic redistribution on INH moiety that would lead to an intramolecular electron transfer to bypass KatG activation. HPLC and EPR studies showed that the INH moiety can be oxidized by superoxide or peroxide yielding similar metabolites and isonicotinoyl radical only when associated to IQG-607, thereby supporting redox-mediated drug activation as a possible mechanism of action. However, IQG-607 was shown to inhibit the in vitro activity of both wild-type and INH-resistant mutant InhA enzymes in the absence of KatG activation. IQG-607 given by the oral route to M. tuberculosis-infected mice reduced lung lesions. Experiments using early and late controls of infection revealed a bactericidal activity for IQG-607. HPLC and voltammetric methods were developed to quantify IQG-607. Pharmacokinetic studies showed short half-life, high clearance, moderate volume of distribution, and low oral bioavailability, which was not altered by feeding. Safety and toxic effects of IQG-607 after acute and 90-day repeated oral administrations in both rats and minipigs showed occurrence of mild to moderate toxic events. Eight multidrug-resistant strains (MDR-TB) were resistant to IQG-607, suggesting an association between katG mutation and increasing MIC values. Whole genome sequencing of three spontaneous IQG-607-resistant strains harbored katG gene mutations. MIC measurements and macrophage infection experiments with a laboratorial strain showed that katG mutation is sufficient to confer resistance to IQG-607 and that the macrophage intracellular environment cannot trigger the self-activation mechanism. Reduced activity of IQG-607 against an M. tuberculosis strain overexpressing S94A InhA mutant protein suggested both the need for KatG activation and InhA as its target. Further efforts are suggested to be pursued toward attempting to translate IQG-607 into a chemotherapeutic agent to treat tuberculosis.

Nonclinical evaluation of IQG-607, an anti-tuberculosis candidate with potential use in combination drug therapy

“…IQG-607, a molecule consisting of a pentacyanoferrate moiety attached to the nitrogen atom of the heterocyclic ring of isoniazid, is an inhibitor of the 2-trans-enoyl-ACP reductase enzyme (Oliveira et al, 2004(Oliveira et al, , 2006Vasconcelos et al, 2008;Abbadi et al, 2018), which blocks the biosynthesis of mycolic acids in M. tuberculosis (Rodrigues-Junior et al, 2014). Importantly, we have reported promising data showing the biological activity of IQG-607 in models of tuberculosis infection both in vitro (Basso et al, 2010;Rodrigues-Junior et al, 2014) and in vivo (Rodrigues-Junior et al, 2012).…”

“…Ideally, a new anti-tuberculosis drug should diminish the length of treatment, lower the dosing frequency, and have lower toxicity issues (Pai et al, 2016;WHO, 2018). Aiming to develop a new oral drug to treat tuberculosis, IQG-607 has been studied for more than fifteen years (Abbadi et al, 2018). Special attention must be taken with drug toxicity and safety pharmacology, mandatory non-clinical studies which must be performed before regulatory applications (Andrade et al, 2016).…”

Pentacyanoferrate(II) complex of pyridine-4- and pyrazine-2-hydroxamic acid as source of HNO: investigation of anti-tubercular and vasodilation activities

“…We should also point out that, in contrast to SNP, whose release of NO also promotes cyanide dissociation, the process is greatly reduced for new pentacyanoferrate complexes. Actually, a quick comparison of the lethal dose of SNP and the pentacyanoferrate(II)-INH complex (IQG607) illustrates this topic (mouse orally administered with SNP and IQG607 LD50 = 61 mg/kg and 2970 mg/ kg, respectively), where SNP is over 48-fold more lethal [14,41]. It is also noteworthy that those values correspond to oral dosages, but considering that pentacyanoferrate(II) complexes are particularly instable in acidic conditionsoccurring in the rats' stomach-leading to decomposition and cyanide release-the real activity level might be even higher with other administration routes.…”

“…Lately, some of the present authors have studied and developed a biomimetic system, as an alternative non enzyme-dependent way to activate the INH antituberculosis pro-drug (KatG = activation enzyme of INH), based on the redox reactivity of a metal complex of INH (called IQG607) in the presence of oxidizing agents such as H 2 O 2 [10][11][12]. The anti-mycobacterial activity (in vitro MIC Mtb = 1.56 μg/mL ~ 3.5 μM) [13], chemical stability, and absence of toxicity (selectivity index SI > 4000, LD 50 > 2000 mg/kg) [14] of the [Fe II (CN) 5 (INH)] 3− complex motivated us to extend this activation approach to heteroaryl hydroxamic acids used as ligands for the development of new HNO donor complexes. Thereby, to prepare HNO donors from [Fe II (CN) 5 (heteroaryl hydroxamic acid)] complexes with wide spectra of biological activities, including antituberculosis, the pyrazine-type nitrogen aryl ring was naturally first selected and used in this study.…”

In silico identification of novel chemical compounds with anti-TB potential for the inhibition of InhA and EthR from Mycobacterium tuberculosis

“…Both require the EthR respectively, leading to disrupting the MA biosynthesis pathway. [ADAPTED FROM: 26,28] formation of covalent adducts with NAD co-factor on oxidative activation to act on the InhA enzyme which is involved in mycolic acid synthesis. (Figure 2) [25,26,27].…”