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，每年造成全球约600万人死亡。即使在美国等发达国家，由于广泛的获得性耐药性，细菌感染也再次被认为是对公共卫生的重大威胁。？内酰胺类抗生素，如青霉素类和头孢菌素类是最常用的抗菌剂。细菌最普遍的耐药机制是什么？-内酰胺类抗生素是生产的吗？-内酰胺酶，能够水解药物，从而使药物失活。虽然克拉维酸和舒巴坦可用于丝氨酸的失活？-内酰胺酶，没有抑制剂可以广泛地对许多不同的金属-？-lactamases (MBL)。MBLs现在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，能水解所有物质吗？-内酰胺类，包括碳青霉烯类（如亚胺培南），这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VIMs）是由可转移的金属-？质粒上的-内酰胺酶基因在世界范围内迅速传播。由于MBL基因，假单胞菌和不动杆菌的一些多重耐药菌株已经显示出对亚胺培南的显著耐药性，治疗这些感染的可用选择很少。然而，由于MBLs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差异很大。显然，迫切需要设计和开发具有广泛而有效的抗mbl活性的新型抑制剂。这种抑制剂的成功开发将为流行耐药革兰氏阴性细菌感染提供新的治疗选择。对于Specific Aim 1，我们将设计和开发一系列基于噻唑烷类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，重要的是满足我们两个假设的要求：(1)该化合物具有强Zn（II）螯合基团，(2)模拟青霉素的结构。这些化合物对许多mbl的活性将被测试，（定量）结构活性关系（SAR）将被分析并用于设计活性更高的化合物。新型MBL抑制剂恢复？-内酰胺耐药细菌也将进行测试。此外，对金属的x射线晶体学研究。-内酰胺酶，IMP-1和Bla2，将与新型抑制剂络合进行。对于Specific Aim 2，将基于初步研究中确定的第二强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，我们建议设计和合成新的双环化合物，不仅非常接近模拟？-内酰胺类，但有一个已知的Zn2+结合基团。

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.