摘要
当今世界范围内,肺结核是世界范围内传染病的第二大致病原因。在过去的二十年中,这种疾病又开始蔓延主要是为多药耐药形式的出现。因此需要新的目标解决不断涌现的细菌耐药性和抗结核药物开发。高效的铁捕获是结核分枝杆菌的发病机制的关键,因为它作为在许多重要的生物过程,包括DNA的生物合成和细胞呼吸的辅助因子。细菌从使用铁素分枝菌素和羧基分枝杆菌素寄主获得铁螯合非血红素铁和血红素铁通过采集系统损坏红细胞释放的吸收。药物发现研究聚焦于MBTI和MBTA的抑制,这是参与分枝菌素生物合成途径的两种酶。特别是,MBTI抑制剂已在体外研究表明,在MBTA抑制剂的活性也在感染小鼠。另一类化合物,在体外和体内MmpL3抑制剂具有抗结核活性,但其作用机制似乎偏离目标。一些发现显示化合物抑制4’- phosphopantetheinyl转移酶被但未进行体内实验。本研究基于抑制剂和基因缺失的研究报告提供的数据,提出靶向铁采集系统可以被认为是一种有前途的抗结核战略。由于他们的冗余性,每个通路的结核分枝杆菌的生存的相对重要性仍需要确定。因此,在体内新的,强有力的和特定的抑制剂研究,需要突出目标选择。
关键词: 肺结核,嗜铁素,分枝菌素的生物合成, (Iso)分支酸类似物,酶抑制,铁螯合剂。
Current Medicinal Chemistry
Title:Iron Acquisition Pathways as Targets for Antitubercular Drugs
Volume: 23 Issue: 35
Author(s): Fiorella Meneghetti, Stefania Villa, Arianna Gelain, Daniela Barlocco, Laurent Roberto Chiarelli, Maria Rosalia Pasca and Luca Costantino
Affiliation:
关键词: 肺结核,嗜铁素,分枝菌素的生物合成, (Iso)分支酸类似物,酶抑制,铁螯合剂。
摘要: Tuberculosis nowadays ranks as the second leading cause of death from an infectious disease worldwide. In the last twenty years, this disease has again started to spread mainly for the appearance of multi-drug resistant forms. Therefore, new targets are needed to address the growing emergence of bacterial resistance and for antitubercular drug development. Efficient iron acquisition is crucial for the pathogenesis of Mycobacterium tuberculosis, because it serves as cofactor in many essential biological processes, including DNA biosynthesis and cellular respiration. Bacteria acquire iron chelating non-heme iron from the host using the siderophore mycobactins and carboxymycobactins and by the uptake of heme iron released by damaged red blood cells, through several acquisition systems. Drug discovery focused its efforts on the inhibition of MbtI and MbtA, which are are two enzymes involved in the mycobactin biosynthetic pathway. In particular, MbtI inhibitors have been studied in vitro, while MbtA inhibitors showed activity also in infected mice. Another class of compounds, MmpL3 inhibitors, showed antitubercular activity in vitro and in vivo, but their mechanism of action seems to be off-target. Some compounds inhibiting 4’-phosphopantetheinyl transferase were discovered but not tested on in vivo assays. The available data reported in this study based on inhibitors and gene deletion studies, suggest that targeting iron acquisition systems could be considered a promising antitubercular strategy. Due to their redundancy, the relative importance of each pathway for Mycobacterium tuberculosis survival has still to be determined. Thus, in vivo studies with new, potent and specific inhibitors are needed to highlight target selection.
Export Options
About this article
Cite this article as:
Fiorella Meneghetti, Stefania Villa, Arianna Gelain, Daniela Barlocco, Laurent Roberto Chiarelli, Maria Rosalia Pasca and Luca Costantino , Iron Acquisition Pathways as Targets for Antitubercular Drugs, Current Medicinal Chemistry 2016; 23 (35) . https://dx.doi.org/10.2174/0929867323666160607223747
DOI https://dx.doi.org/10.2174/0929867323666160607223747 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Mycobacterium tuberculosis and Dendritic Cells: Whos Manipulating Whom?
Current Immunology Reviews (Discontinued) Clinical Presentation, Treatment Outcome and Survival Among the HIV Infected Children with Culture Confirmed Tuberculosis
Current HIV Research Crosstalk Between The Immune Receptors and Gut Microbiota
Current Protein & Peptide Science Balancing the Double-Edged Sword: Metal Ion Homeostasis and the Ulcer Bug
Current Medicinal Chemistry The IL23/Th17 Pathway as a Therapeutic Target in Chronic Inflammatory Diseases
Inflammation & Allergy - Drug Targets (Discontinued) Antibiotic use Evaluation in Hospitalized Pediatric Patients with Respiratory Tract Infections: A Retrospective Chart Review Study
Current Drug Safety Cutaneous Adverse Drug Reactions Caused by Antituberculosis Drugs
Inflammation & Allergy - Drug Targets (Discontinued) Bringing Down the Wall of the Mycobacterium tuberculosis Fortress: Old and New Inhibitors of Mycolic Acid Biosynthesis
Current Respiratory Medicine Reviews Cyclospora Cayetanensis: A Review, Focusing on What Some of the Remaining Questions about Cyclosporiasis
Infectious Disorders - Drug Targets Polymer Based Drug Delivery Systems for Mycobacterial Infections
Current Drug Delivery Lung Cancer Chemotherapy, New Treatment and Related Patents
Recent Patents on Anti-Cancer Drug Discovery A Key Role for Altered Dendritic Cell Functioning in the Impaired Immunity Seen in Aged Individuals
Current Immunology Reviews (Discontinued) Discrimination of Chemical Profiles of Some Bacterial Species by Analyzing Culture Headspace Air Samples Using TD-GC/MS
Current Analytical Chemistry Blood Pressure Measurement: Lessons Learned from Our Ancestors
Current Pharmaceutical Design Secretory Leukocyte Protease Inhibitor: More than Just A Protease Inhibitor
Current Immunology Reviews (Discontinued) A New Battlefield Towards Global Health in 21<sup>st</sup> Century: Clinical Research Networks
Applied Clinical Research, Clinical Trials and Regulatory Affairs Role of FoxP3<sup>+</sup> Treg Cells Mediating Immune Suppression in Leprosy
Current Immunology Reviews (Discontinued) Biotechnology in the Development of New Vaccines and Diagnostic Reagents Against Tuberculosis
Current Pharmaceutical Biotechnology Inflammatory Bowel Disease: New Therapeutic Options in the Post Anti-TNFα Era
Current Drug Metabolism Inhaled Biologics: From Preclinical to Product Approval
Current Pharmaceutical Design