Novel Metallo-beta-lactamase Inhibitors

描述（由申请人提供）：细菌感染是人类死亡的头号原因，每年在全世界造成约600万人死亡。即使在发达国家，如美国，细菌感染再次被认为是对公共卫生的重大威胁，因为广泛的获得性耐药性。?-内酰胺类抗生素如青霉素和头孢菌素是最常用的抗微生物剂。细菌耐药的最普遍机制是？内酰胺类抗生素是生产？-能够水解并从而降解药物的内酰胺酶。虽然克拉维酸和舒巴坦可用于丝氨酸？内酰胺酶，没有抑制剂是广泛有效的对许多不同的金属-？内酰胺酶（MBL）。MBLs现在已被认为是一种新兴的临床威胁，因为这些酶，不像丝氨酸？内酰胺酶，能够水解基本上所有的？内酰胺类，包括碳青霉烯类（例如，亚胺培南），其是几种多重耐药革兰氏阴性细菌感染的最后手段药物。此外，许多MBL（例如，IMP和VIM）由可转移金属-？-质粒上的内酰胺酶基因在世界范围内迅速传播。假单胞菌属和不动杆菌属的一些多重耐药菌株。由于MBL基因，已经显示出对亚胺培南的显著抗性，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低，目前的抑制剂的活性谱在酶之间变化很大。显然，迫切需要设计和开发对MBL具有广泛和有效活性的新型抑制剂。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，符合我们两个假设的要求：（1）该化合物具有强Zn（II）螯合基团和（2）模拟青霉素的结构。将测试这些化合物对许多MBL的活性，并分析（定量）结构活性关系（SAR），并用于设计具有改善活性的化合物。新型MBL抑制剂恢复？-并会测试耐内酰胺细菌。此外，X射线晶体学研究的金属-？-将进行与新型抑制剂复合的内酰胺酶IMP-1和Bla 2。对于具体目标2，将根据初步研究中确定的第二大有效化合物设计和开发另一系列化合物。此外，基于上述两个假设，我们提出了设计和合成新的双环化合物，这些化合物不仅与？内酰胺，但具有已知的Zn 2+结合基团。 公共卫生相关性：许多细菌现在已经对碳青霉烯类抗生素（一种用作最后药物的青霉素类抗生素）产生耐药性，因为它们获得了一种称为金属β-内酰胺酶的蛋白质。拟议的研究旨在产生新的潜在佐剂抗生素，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。

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.