Novel Metallo-beta-lactamase Inhibitors

新型金属-β-内酰胺酶抑制剂

• 批准号: 8075426
• 负责人: Yongcheng Song
• 金额: $ 19万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8075426
• 关键词: 2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole; Acinetobacter; Active Sites; Adjuvant; Amino Acid Sequence Homology; Anti-Bacterial Agents; Antibiotics; Bacteria; Bacterial Infections; Bicyclo Compounds; Binding; Biological; Carbapenems; Cells; Cephalosporins; Cessation of life; Chemistry; Clavulanic Acids; Clinical; Complex; Crystallography; Developed Countries; Development; Drug Design; Drug resistance; Enzymes; Epidemic; Genes; Goals; Gram-Negative Bacterial Infections; Human; Hydrolase; Imipenem; Infection; Ions; Lactamase; Lactams; Lead; Libraries; Matrix Metalloproteinases; Metals; Monobactams; Multi-Drug Resistance; Penicillins; Pharmaceutical Preparations; Plasmids; Predisposition; Production; Proteins; Pseudomonas; Pseudomonas aeruginosa; Public Health; Quantitative Structure-Activity Relationship; Research; Resistance; Resort; Roentgen Rays; Series; Serine; Site-Directed Mutagenesis; Structure; Structure-Activity Relationship; Sulbactam; Synthesis Chemistry; Testing; Toxic effect; Work; World Health Organization; Zinc; antimicrobial drug; bacterial resistance; base; beta-Lactamase; cell growth; design; drug discovery; enzyme activity; improved; inhibitor/antagonist; killings; meetings; metalloenzyme; neurotensin mimic 2; novel; public health relevance; resistant strain; small molecule

DESCRIPTION (provided by applicant): Bacterial infections are the number one cause of human deaths, killing ~6 million people each year worldwide. Even in developed countries, such as the US, bacterial infections are once again recognized as a significant threat to public health because of widespread, acquired drug resistance. ?-Lactam antibiotics such as penicillins and cephalosporins are among the most often used antimicrobial agents. The most prevalent mechanism of bacterial resistance to ?-lactam antibiotics is the production of ?-lactamases that are able to hydrolyze and thereby inactivate the drugs. Although clavulanic acid and sulbactam are available for inactivation of serine ?-lactamases, no inhibitors are available that are broadly active against the many distinct metallo-?-lactamases (MBL). MBLs have now been recognized as an emerging clinical threat in that these enzymes, unlike serine ?-lactamases, are able to hydrolyze essentially all ?-lactams, including carbapenems (e.g., imipenem) which are last resort drugs for several multidrug resistant Gram-negative bacterial infections. In addition, many MBLs (e.g., IMPs and VIMs) are encoded by transferable metallo-?-lactamase genes on plasmids that have disseminated quickly worldwide. Some multidrug resistant strains of Pseudomonas and Acinetobacter spp. have already demonstrated significant resistance against imipenem due to MBL genes and there are few options available to treat these infections. However, due to low amino acid sequence homology among MBLs, the spectrum of activity of current inhibitors varies considerably among enzymes. It is apparent that a pressing need exists to design and develop novel inhibitors that have broad and potent activity against MBLs. The successful development of such inhibitors would offer new treatment options for epidemic drug resistant Gram-negative bacterial infections. For Specific Aim 1, we will design and develop a series of compounds based on a thiazolidine MBL inhibitor, which is our most potent compound in Preliminary studies and, importantly, meets both requirements of our two hypotheses: (1) the compound has a strong Zn(II) chelating group and (2) mimics the structure of penicillin. The activity of these compounds against a number of MBLs will be tested and (quantitative) structure activity relationships (SAR) be analyzed and used to design compounds with improved activity. The ability of the novel MBL inhibitors to restore the susceptibility of ?-lactam resistant bacteria will also be tested. In addition, x-ray crystallographic studies of metallo-?-lactamases, IMP-1 and Bla2, complexed with the novel inhibitors will be performed. For Specific Aim 2, another series of compounds will be designed and developed based on the second most potent compound identified in preliminary studies. In addition, based on the two hypotheses stated above, we propose to design and synthesize novel bicyclic compounds that not only closely mimic the structures of ?-lactams, but have a known Zn2+-binding group. PUBLIC HEALTH RELEVANCE: Many bacteria have now become resistant to carbapenems, a class of penicillin-like antibiotics used as last resort drugs, because they have acquired a protein called metallo-beta-lactamase. The proposed research is designed to lead to new potential adjuvant antibiotics that can inhibit the activity of this protein and thus restore the susceptibility of these bacteria to carbapenems.

描述（由申请人提供）：细菌感染是人类死亡的第一大原因，全世界每年约有 600 万人死亡。即使在美国等发达国家，由于广泛的后天耐药性，细菌感染也再次被认为是对公共健康的重大威胁。 β-内酰胺抗生素，例如青霉素和头孢菌素是最常用的抗菌剂。细菌对β-内酰胺抗生素产生耐药性的最普遍机制是产生β-内酰胺酶，该酶能够水解并从而使药物失活。尽管克拉维酸和舒巴坦可用于灭活丝氨酸β-内酰胺酶，但尚无对许多不同的金属-β-内酰胺酶（MBL）具有广泛活性的抑制剂。 MBL 现在已被认为是一种新兴的临床威胁，因为这些酶与丝氨酸 β-内酰胺酶不同，能够水解基本上所有 β-内酰胺，包括碳青霉烯类（例如亚胺培南），碳青霉烯类是治疗几种多重耐药革兰氏阴性细菌感染的最后手段。此外，许多 MBL（例如 IMP 和 VIM）是由质粒上的可转移金属-β-内酰胺酶基因编码的，这些基因已在全球范围内迅速传播。一些假单胞菌属和不动杆菌属的多重耐药菌株。由于 MBL 基因，已经表现出对亚胺培南的显着耐药性，并且几乎没有可用于治疗这些感染的选择。然而，由于 MBL 之间的氨基酸序列同源性较低，当前抑制剂的活性谱在酶之间存在很大差异。显然，迫切需要设计和开发具有广泛而有效的 MBL 活性的新型抑制剂。此类抑制剂的成功开发将为流行性耐药革兰氏阴性细菌感染提供新的治疗选择。对于具体目标 1，我们将设计和开发一系列基于噻唑烷 MBL 抑制剂的化合物，这是我们在初步研究中最有效的化合物，重要的是，它满足我们两个假设的两个要求：(1) 该化合物具有强的 Zn(II) 螯合基团，(2) 模仿青霉素的结构。将测试这些化合物针对多种 MBL 的活性，并分析（定量）结构活性关系 (SAR)，并用于设计具有改进活性的化合物。新型 MBL 抑制剂恢复 β-内酰胺耐药细菌敏感性的能力也将得到测试。此外，还将对与新型抑制剂复合的金属-β-内酰胺酶、IMP-1 和 Bla2 进行 X 射线晶体学研究。对于具体目标 2，将根据初步研究中确定的第二个最有效的化合物来设计和开发另一系列化合物。此外，基于上述两个假设，我们建议设计和合成新型双环化合物，其不仅密切模仿β-内酰胺的结构，而且具有已知的Zn2+结合基团。 公共健康相关性：许多细菌现在已经对碳青霉烯类抗生素产生耐药性，碳青霉烯类抗生素是一类用作最后手段的青霉素类抗生素，因为它们获得了一种称为金属-β-内酰胺酶的蛋白质。拟议的研究旨在开发新的潜在辅助抗生素，可以抑制这种蛋白质的活性，从而恢复这些细菌对碳青霉烯类的敏感性。