Inhibitors of Mycobacterium tuberculosis FAS-II dehydratases

结核分枝杆菌 FAS-II 脱水酶抑制剂

• 批准号: 10190829
• 负责人: Mary Jackson
• 金额: $ 20.02万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-12 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10190829
• 关键词: AIDS/HIV problem; Accounting; Anabolism; Animal Model; Antitubercular Agents; Applications Grants; Bacillus; Biological; Budgets; Bypass; Cell Death; Cessation of life; Chemicals; Clinical Treatment; Collaborations; Colorado; Crystallization; Dehydration; Development; Dose; Drug Kinetics; Drug Targeting; Drug resistance in tuberculosis; Ensure; Enzyme Inhibition; Enzymes; Evaluation; Frequencies; Generations; Goals; HIV; Hydro-Lyases; In Vitro; Investigation; Knowledge; Laboratories; Lead; Metabolic; Mixed Function Oxygenases; Modification; Molecular Mechanisms of Action; Multi-Drug Resistance; Mus; Mutation; Mycobacterium tuberculosis; Mycolic Acid; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Poverty; Predisposition; Prodrugs; Property; Public Health; Resistance; Series; South Africa; Specificity; Structure; System; Testing; Tuberculosis; Universities; analog; bactericide; base; design; drug candidate; drug development; drug discovery; efficacy study; efficacy testing; enzyme activity; extensive drug resistance; fatty acid synthase II; improved; in vivo; inhibitor/antagonist; interest; mouse model; multidisciplinary; novel; novel therapeutics; pandemic disease; pre-clinical; resistance mechanism; resistant strain; safety study; safety testing; scaffold; synergism; targeted treatment; therapeutically effective; thiocarlide; trend; tuberculosis drugs; tuberculosis treatment

Project Summary Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a major public health problem worldwide and the most common presenting illness among people living with HIV accounting for one in four HIV/AIDS-associated deaths. The continuing rise of multidrug-resistant strains of Mtb makes the development of new effective anti-TB drugs a high priority. In this context, re-examining the molecular mechanism of action of established antitubercular drugs that target the same well-validated biosynthetic pathway as front-line anti- TB agents but at a distinct catalytic step, thereby bypassing widespread resistance mechanisms, could have a major impact on the treatment of drug-resistant TB. Two such prodrugs previously used in the clinical treatment of TB, Isoxyl (ISO) and Thiacetazone (TAC), have been the object of our investigations. We identified the essential FAS-II dehydratase, HadAB, as the enzyme targeted by both ISO and TAC to inhibit mycolic acid biosynthesis and elucidated some of the most common mechanisms of resistance associated with the inhibition of this enzyme in Mtb. Recent collaborative studies between Colorado State University and the University of Cape Town Drug Discovery and Development Centre (H3D) (South Africa), have led to the discovery of a new generation of HadAB inhibitors, structurally unrelated to ISO and TAC, that displays potent activity against whole Mtb bacilli. Preliminary mode of action studies indicate that these compounds: (i) unlike ISO and TAC, do not require activation by the monooxygenase EthA; (ii) interact with HadAB differently from the former drugs; and (iii) that a subset of them have the ability to inhibit the second dehydratase of FAS-II, HadBC, which accounts for some of the resistance mechanisms associated with HadAB inhibition in Mtb. As a result, this new compound series has the potential to bypass some of the most common resistance mechanisms associated with the chemical inhibition of Mtb HadAB. This proposal aims to develop novel effective therapeutics based on H3D’s compounds with which to treat Mtb infections. This goal will be achieved by optimizing existing hits through chemical analoging (Aim 1), biological profiling (Aim 2) and in vivo efficacy testing of emerging leads (Aim 3).

项目概要 由结核分枝杆菌 (Mtb) 引起的结核病 (TB) 仍然是一个主要的公共卫生问题 全世界艾滋病毒感染者中最常见的疾病，占四分之一 与艾滋病毒/艾滋病相关的死亡。 Mtb多重耐药菌株的持续上升使得发展 开发新的有效抗结核药物是当务之急。在此背景下，重新审视作用的分子机制 已建立的抗结核药物的靶点与一线抗结核药物相同，经过充分验证的生物合成途径 结核病药物但处于独特的催化步骤，从而绕过广泛的耐药机制，可能会产生 对耐药结核病的治疗产生重大影响。两种此类前药曾用于临床 结核病治疗药物异氧基 (ISO) 和硫醋酮 (TAC) 一直是我们研究的对象。我们 确定必需的 FAS-II 脱水酶 HadAB 作为 ISO 和 TAC 的靶向酶来抑制 分枝菌酸生物合成并阐明了与分枝菌酸相关的一些最常见的耐药机制 Mtb 中这种酶的抑制。 科罗拉多州立大学和开普敦药物大学最近的合作研究 发现和开发中心（H3D）（南非），发现了新一代 HadAB 抑制剂在结构上与 ISO 和 TAC 无关，对整个 Mtb 杆菌表现出有效的活性。 初步作用模式研究表明，这些化合物：(i) 与 ISO 和 TAC 不同，不需要 由单加氧酶 EthA 激活； (ii) 与 HadAB 的相互作用不同于以前的药物； (iii) 其中一部分能够抑制 FAS-II 的第二种脱水酶 HadBC，这可以解释一些 与 Mtb 中 HadAB 抑制相关的耐药机制。因此，这个新的化合物系列 有可能绕过与化学品相关的一些最常见的耐药机制 Mtb HadAB 的抑制。 该提案旨在基于 H3D 的化合物开发新的有效疗法来治疗 Mtb 感染。这一目标将通过化学模拟（目标 1）、生物模拟等方式优化现有命中来实现。 新兴先导化合物的分析（目标 2）和体内功效测试（目标 3）。

项目成果

1,3-Diarylpyrazolyl-acylsulfonamides Target HadAB/BC Complex in Mycobacterium tuberculosis.

• DOI: 10.1021/acsinfecdis.2c00392
• 发表时间: 2022-11-11
• 期刊: ACS INFECTIOUS DISEASES
• 影响因子: 5.3
• 作者: Singh, Vinayak;Grzegorzewicz, Anna E.;Fienberg, Stephen;Muller, Rudolf;Khonde, Lutete Peguy;Sanz, Olalla;Alfonso, Salvatore;Urones, Beatriz;Drewes, Gerard;Bantscheff, Marcus;Ghidelli-Disse, Sonja;Ioerger, Thomas R.;Angala, Bhanupriya;Liu, Jiuyu;Lee, Richard E.;Sacchettini, James C.;Krieger, Inna, V;Jackson, Mary;Chibale, Kelly;Ghorpade, Sandeep R.
• 通讯作者: Ghorpade, Sandeep R.

Mycobacterial Epoxide Hydrolase EphD Is Inhibited by Urea and Thiourea Derivatives.

• DOI: 10.3390/ijms22062884
• 发表时间: 2021-03-12
• 期刊: International journal of molecular sciences
• 影响因子: 5.6
• 作者: Madacki J;Kopál M;Jackson M;Korduláková J
• 通讯作者: Korduláková J

Lack of Specificity of Phenotypic Screens for Inhibitors of the Mycobacterium tuberculosis FAS-II System.

结核分枝杆菌 FAS-II 系统抑制剂的表型筛选缺乏特异性。

• DOI: 10.1128/aac.01914-20
• 发表时间: 2020
• 期刊: Antimicrobial agents and chemotherapy
• 影响因子: 4.9
• 作者: Grzegorzewicz,AnnaE;Lelièvre,Joël;Esquivias,Jorge;Angala,Bhanupriya;Liu,Jiuyu;Lee,RichardE;McNeil,MichaelR;Jackson,Mary
• 通讯作者: Jackson,Mary