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Insights on the Mechanism of Action of INH-C10 as an Antitubercular Prodrug
Molecular Pharmaceutics ( IF 4.9 ) Pub Date : 2017-11-13 00:00:00 , DOI: 10.1021/acs.molpharmaceut.7b00719 Diogo Vila-Viçosa 1 , Bruno L. Victor 1 , Jorge Ramos 2 , Diana Machado 2 , Miguel Viveiros 2 , Jacek Switala 3 , Peter C. Loewen 3 , Ruben Leitão 1, 4 , Filomena Martins 1 , Miguel Machuqueiro 1
Molecular Pharmaceutics ( IF 4.9 ) Pub Date : 2017-11-13 00:00:00 , DOI: 10.1021/acs.molpharmaceut.7b00719 Diogo Vila-Viçosa 1 , Bruno L. Victor 1 , Jorge Ramos 2 , Diana Machado 2 , Miguel Viveiros 2 , Jacek Switala 3 , Peter C. Loewen 3 , Ruben Leitão 1, 4 , Filomena Martins 1 , Miguel Machuqueiro 1
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Tuberculosis remains one of the top causes of death worldwide, and combating its spread has been severely complicated by the emergence of drug-resistance mutations, highlighting the need for more effective drugs. Despite the resistance to isoniazid (INH) arising from mutations in the katG gene encoding the catalase-peroxidase KatG, most notably the S315T mutation, this compound is still one of the most powerful first-line antitubercular drugs, suggesting further pursuit of the development of tailored INH derivatives. The N′-acylated INH derivative with a long alkyl chain (INH-C10) has been shown to be more effective than INH against the S315T variant of Mycobacterium tuberculosis, but the molecular details of this activity enhancement are still unknown. In this work, we show that INH N′-acylation significantly reduces the rate of production of both isonicotinoyl radical and isonicotinyl–NAD by wild type KatG, but not by the S315T variant of KatG mirroring the in vivo effectiveness of the compound. Restrained and unrestrained MD simulations of INH and its derivatives at the water/membrane interface were performed and showed a higher preference of INH-C10 for the lipidic phase combined with a significantly higher membrane permeability rate (27.9 cm s–1), compared with INH-C2 or INH (3.8 and 1.3 cm s–1, respectively). Thus, we propose that INH-C10 is able to exhibit better minimum inhibitory concentration (MIC) values against certain variants because of its better ability to permeate through the lipid membrane, enhancing its availability inside the cell. MIC values of INH and INH-C10 against two additional KatG mutations (S315N and D735A) revealed that some KatG variants are able to process INH faster than INH-C10 into an effective antitubercular form (wt and S315N), while others show similar reaction rates (S315T and D735A). Altogether, our results highlight the potential of increased INH lipophilicity for treating INH-resistant strains.
中文翻译:
关于INH-C 10作为抗结核前药的作用机理的见解
结核病仍然是世界范围内最主要的死亡原因之一,由于耐药性突变的出现,遏制结核病的传播已变得极为复杂,这凸显了对更有效药物的需求。尽管由于编码过氧化氢酶过氧化物酶KatG的katG基因突变引起的对异烟肼(INH)的耐药性,尤其是S315T突变,该化合物仍是最强大的一线抗结核药物之一,表明对它的发展有进一步的追求。量身定制的INH衍生物。所述Ñ '具有长烷基链(INH-C -acylated INH衍生物10)已被证明比INH是更有效的对抗的S315T变体结核分枝杆菌,但这种活性增强的分子细节仍然未知。在这项工作中,我们表明,INH N'-酰化作用显着降低了野生型KatG产生异烟酰自由基和异烟碱-NAD的产生速率,但没有降低KatG的S315T变体,从而反映了该化合物的体内有效性。在水/膜界面对INH及其衍生物进行了束缚和不受束缚的MD模拟,结果表明,与脂质相相比,INH-C 10对脂相的偏爱更高,而膜通透率(27.9 cm s –1)则要高得多。 INH-C 2或INH(分别为3.8和1.3 cm s –1)。因此,我们建议INH-C 10由于其更好的渗透脂质膜的能力,增强了其在细胞内的利用率,因此能够针对某些变体表现出更好的最小抑菌浓度(MIC)值。针对另外两个KatG突变(S315N和D735A)的INH和INH-C 10的MIC值显示,某些KatG变体能够比INH-C 10更快地将INH加工成有效的抗结核形式(wt和S315N),而其他一些表现出相似的效果反应速率(S315T和D735A)。总而言之,我们的结果突出了提高INH亲脂性治疗INH耐药菌株的潜力。
更新日期:2017-11-14
中文翻译:
关于INH-C 10作为抗结核前药的作用机理的见解
结核病仍然是世界范围内最主要的死亡原因之一,由于耐药性突变的出现,遏制结核病的传播已变得极为复杂,这凸显了对更有效药物的需求。尽管由于编码过氧化氢酶过氧化物酶KatG的katG基因突变引起的对异烟肼(INH)的耐药性,尤其是S315T突变,该化合物仍是最强大的一线抗结核药物之一,表明对它的发展有进一步的追求。量身定制的INH衍生物。所述Ñ '具有长烷基链(INH-C -acylated INH衍生物10)已被证明比INH是更有效的对抗的S315T变体结核分枝杆菌,但这种活性增强的分子细节仍然未知。在这项工作中,我们表明,INH N'-酰化作用显着降低了野生型KatG产生异烟酰自由基和异烟碱-NAD的产生速率,但没有降低KatG的S315T变体,从而反映了该化合物的体内有效性。在水/膜界面对INH及其衍生物进行了束缚和不受束缚的MD模拟,结果表明,与脂质相相比,INH-C 10对脂相的偏爱更高,而膜通透率(27.9 cm s –1)则要高得多。 INH-C 2或INH(分别为3.8和1.3 cm s –1)。因此,我们建议INH-C 10由于其更好的渗透脂质膜的能力,增强了其在细胞内的利用率,因此能够针对某些变体表现出更好的最小抑菌浓度(MIC)值。针对另外两个KatG突变(S315N和D735A)的INH和INH-C 10的MIC值显示,某些KatG变体能够比INH-C 10更快地将INH加工成有效的抗结核形式(wt和S315N),而其他一些表现出相似的效果反应速率(S315T和D735A)。总而言之,我们的结果突出了提高INH亲脂性治疗INH耐药菌株的潜力。