The emergence of tuberculosis (TB) produced by multi-drug resistance (MDR) and extensively-drug resistance (XDR) Mycobacterium tuberculosis (Mtb), encourages the development of new antituberculous compounds, as well as the identification of novel drug targets. In this regard, plasma membrane P-type ATPases are interesting targets because they play a crucial role in ion homeostasis and mycobacterial survival. We focused on Mtb CtpF, a calcium P-type ATPase that responds to a broad number of intraphagosomal conditions, as a novel target. In this study, we evaluated the capacity of cyclopiazonic acid (CPA), a well-known inhibitor of the sarco-endoplasmic reticulum Ca2+-ATPase (SERCA), to inhibit the ATPase activity of CtpF and the Mtb growth demonstrating that CtpF is a druggable target. A homology modeling of CtpF was generated for molecular docking studies of CtpF with CPA and key pharmacophoric features were identified, which were used to perform a pharmacophore-based virtual screening of the ZINC database, and to identify CtpF inhibitor candidates. Molecular docking-based virtual screening and MM-BGSA calculations of candidates allowed identifying six compounds with the best binding energies. The compounds displayed in vitro minimum inhibitory concentrations (MIC) ranging from 50 to 100 μg/mL, growth inhibitions from 29.5 to 64.0% on Mtb, and inhibitions of Ca2+-dependent ATPase activity in Mtb membrane vesicles (IC50) ranging from 4.1 to 35.8 μM. The compound ZINC63908257 was the best candidate by displaying a MIC of 50 μg/mL and a Ca2+ P-type ATPase inhibition of 45% with IC50 = 4.4 μM. Overall, the results indicate that CtpF is a druggable target for designing new antituberculous compounds.

中文翻译：

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鉴定结核分枝杆菌CtpF作为设计新的抗结核化合物的靶标。

由多药耐药性（MDR）和广泛耐药性（XDR）结核分枝杆菌（Mtb）产生的结核病（TB）的出现，鼓励了新的抗结核化合物的开发以及新药靶标的鉴定。在这方面，质膜P型ATP酶是有趣的靶标，因为它们在离子稳态和分枝杆菌存活中起着至关重要的作用。我们专注于Mtb CtpF，这是一种钙P型ATP酶，可应对多种吞噬内条件，是一种新型靶标。在这项研究中，我们评估了著名的肌内质网Ca2 + -ATPase（SERCA）抑制剂环吡嗪酸（CPA）抑制CtpF和Mtb生长的ATPase活性，证明CtpF是可药用的目标。生成了CtpF的同源性模型，用于CtpF与CPA的分子对接研究，并鉴定了关键药效学特征，这些特征用于对ZINC数据库进行基于药效学的虚拟筛选，并鉴定CtpF抑制剂候选物。基于分子对接的虚拟筛选和MM-BGSA计算候选物，可以鉴定出具有最佳结合能的六种化合物。这些化合物的体外最低抑制浓度（MIC）为50至100μg/ mL，对Mtb的生长抑制率为29.5至64.0％，对Mtb膜囊泡的Ca2 +依赖性ATPase活性的抑制率（IC50）为4.1至35.8。微米 化合物ZINC63908257是最佳候选化合物，其MIC为50μg/ mL，对Ca2 + P型ATP酶的抑制率为45％，IC50 = 4.4μM。全面的，