Preserving beta-lactam utility against pathogens producing all classes of beta-la

保留 β-内酰胺的效用，对抗产生所有类别 β-la 的病原体

• 批准号: 8200421
• 负责人: Christopher John Burns
• 金额: $ 30万
• 依托单位: VENATORX PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8200421
• 关键词: ADME Study; Accounting; Address; Anti-Bacterial Agents; Antibiotics; Applications Grants; Aztreonam; Bacteria; Biological; Boronic Acids; Carbapenems; Cells; Cephalosporins; Chemicals; Clavulanic Acids; Clinical; Development; Drug Formulations; Enterobacteriaceae; Enterobacteriaceae Infections; Enzymes; Epidemiology; Escherichia coli; Frequencies; Future; General Ward; Generations; Goals; Grant; Growth; Hospitals; Hydrolysis; In Vitro; Infection; Inhibitory Concentration 50; Klebsiella pneumonia bacterium; Lactamase; Lactams; Lead; Light; Mammalian Cell; Modeling; Monobactams; Multi-Drug Resistance; Mus; Naturopathic Doctor; Penicillins; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Phase; Protein Binding; Relative (related person); Reporting; Research; Risk; Septicemia; Series; Serine; Small Business Innovation Research Grant; Solubility; Solutions; Staging; Tazobactam; Testing; Time; Toxicology; Variant; Water; Zinc; analog; aqueous; base; beta-Lactams; candidate selection; cytotoxicity; cytotoxicity test; design; enzyme activity; in vivo; inhibitor/antagonist; lead series; mouse model; novel; pathogen; pre-clinical; pressure; resistant strain; response; scale up; success

DESCRIPTION (provided by applicant): This Phase I SBIR Grant focuses on advancement of a new class of inhibitors of serine-based b-lactamases (Ambler classes A, C and D), for combination with the only subclass of b-lactams (the monobactams) that are not sensitive to zinc-based enzymes (Ambler Class B). Full coverage against all classes of b-lactamases is critically important in light of the alarming increase in clinical strains of Enterobacteriaceae carrying mixed serine- and metallo-enzymes. The combination product will have utility both in the general ward and ICU for treating infections with multi-drug resistant gram negative pathogens. b-Lactam antibiotics, including penicillins, cephalosporins, monobactams and carbapenems, are the most widely used antibiotic class in the U.S., accounting for more than 50% of antibacterial prescriptions. In response to pressure from 7 decades of b-lactam usage, bacteria have evolved to produce enzymes (b- lactamases) that efficiently hydrolyze and inactivate b-lactams. The past 30 years has seen the explosive growth of variants of these enzymes, with over 890 unique b-lactamases identified in naturally occurring bacterial isolates to date. Legacy inhibitors of b-lactamases (e.g., clavulanic acid and tazobactam) were designed to address enzymes that predominated at the time of their release; i.e., Class A extended spectrum b-lactamases). They do not inhibit class B, C or D enzymes, and they are inactive against Class A carbapenemases. Indeed, no relevant inhibitors of class B metallo-b-lactamases (MBLs) are in development or have been reported. The only option for preserving the b-lactam class of antibiotics in Enterobacteriaceae expressing both serine- and metallo-b-lactamases is to pair a new generation, broad-spectrum BLI that covers all serine-b-lactamases with a monobactam (e.g., Aztreonam: Azt) that is impervious to MBLs. We have identified an Advanced Lead series of boronic-acid based BLIs with coverage extending across Ambler Class A, C and D enzymes. When tested with Azt, the combination product demonstrates potent inhibition of carbapenem-resistant strains of Enterobacteriaceae that express both an MBL and at least one serine-b-lactamase. The overall goal of this Phase I SBIR grant application is to continue chemical optimization of this novel series in order to deliver Finalist compounds in advance of Preclinical Candidate selection. Such Finalists will have broad coverage of serine-b-lactamases and will rescue Azt in strains of Enterobacteriaceae that express both a Class B and a Class A, C and/or D enzyme(s). They will have high aqueous solubility (for formulating with water-soluble b-lactam antibiotics) and will rescue Azt in lethal mouse models of multi-drug resistant Enterobacteriaceae infection. Success in these endeavors will trigger the submission of a Phase II application that will drive the Finalists to Preclinical Candidate Selection and then through Preclinical Development (GMP scale-up, GLP toxicology, formulation development, epidemiology, etc), ultimately to IND submission. PUBLIC HEALTH RELEVANCE: The alarming expansion of strains of Enterobacteriaceae that co-express both metallo- and serine-b- lactamases places the future utility of the b-lactam class of antibiotics at significant risk. There is no currently- available combination b-lactam/b-lactamase inhibitor (BLI) product approved or in development that addresses this growing threat. Herein we propose to advance a new combination platform: a novel class of BLIs with activity against all Ambler classes of serine-b-lactamases (Classes A, C, and D) in combination with a monobactam antibiotic (aztreonam) that is intrinsically stable to hydrolysis by metallo-b-lactamases (Class B). Success would provide the first b-lactam/BLI product combination to cover Enterobacteriaceae expressing all types of b-lactamases. Such a product would dramatically enhance the clinician's armamentarium in the general ward and ICU against multi-drug resistant gram negative pathogens.

描述（由申请人提供）：本期 SBIR 资助重点关注开发一类新的基于丝氨酸的 β-内酰胺酶抑制剂（Ambler A、C 和 D 类），与唯一的 β-内酰胺亚类（Ambler 类 A、C 和 D）组合。 monobactams）对锌基酶（Ambler B 类）不敏感。鉴于携带混合丝氨酸酶和金属酶的肠杆菌科临床菌株的惊人增加，全面覆盖所有类别的 β-内酰胺酶至关重要。该组合产品将适用于普通病房和重症监护病房，用于治疗多重耐药革兰氏阴性病原体感染。 β-内酰胺类抗生素，包括青霉素、头孢菌素、单环菌素和碳青霉烯类，是美国使用最广泛的抗生素类别，占抗菌处方的 50% 以上。为了应对 7 年来 β-内酰胺使用带来的压力，细菌已经进化出能够产生有效水解和灭活 β-内酰胺的酶（β-内酰胺酶）。在过去的 30 年里，这些酶的变体呈爆炸式增长，迄今为止，在天然存在的细菌分离物中已鉴定出 890 多种独特的 β-内酰胺酶。传统的 β-内酰胺酶抑制剂（例如克拉维酸和他唑巴坦）旨在解决释放时占主导地位的酶；即 A 类广谱 β-内酰胺酶）。它们不抑制 B、C 或 D 类酶，并且对 A 类碳青霉烯酶没有活性。事实上，目前还没有相关的 B 类金属-b-内酰胺酶 (MBL) 抑制剂正在开发或已被报道。在同时表达丝氨酸和金属 β 内酰胺酶的肠杆菌科细菌中保留 β 内酰胺类抗生素的唯一选择是将覆盖所有丝氨酸 β 内酰胺酶的新一代广谱 BLI 与单菌酰胺（例如氨曲南）配对。 : Azt) 不受 MBL 影响。我们已经确定了 Advanced Lead 系列基于硼酸的 BLI，其覆盖范围涵盖 Ambler A、C 和 D 类酶。当与 Azt 一起测试时，该组合产品显示出对同时表达 MBL 和至少一种丝氨酸-b-内酰胺酶的肠杆菌科碳青霉烯类耐药菌株的有效抑制作用。第一阶段 SBIR 拨款申请的总体目标是继续对这一新颖系列进行化学优化，以便在临床前候选药物选择之前提供入围化合物。这些决赛入围者将广泛覆盖丝氨酸-b-内酰胺酶，并将拯救表达 B 类和 A 类、C 和/或 D 类酶的肠杆菌科菌株中的 Azt。它们具有高水溶性（用于与水溶性 β-内酰胺抗生素一起配制），并且可以在多重耐药肠杆菌科感染的致死小鼠模型中拯救 Azt。这些努力的成功将触发 II 期申请的提交，该申请将推动决赛入围者进行临床前候选药物选择，然后通过临床前开发（GMP 放大、GLP 毒理学、制剂开发、流行病学等），最终提交 IND。 公共健康相关性：同时表达金属-和丝氨酸-β-内酰胺酶的肠杆菌科菌株的惊人扩张使β-内酰胺类抗生素的未来应用面临重大风险。目前尚无已批准或正在开发的 β-内酰胺/β-内酰胺酶抑制剂 (BLI) 组合产品可以解决这一日益严重的威胁。在此，我们建议推进一个新的组合平台：一类新型 BLI，具有对抗所有 Ambler 类丝氨酸-b-内酰胺酶（A、C 和 D 类）的活性，与本质上稳定的单菌素抗生素（氨曲南）相结合。金属-b-内酰胺酶水解（B 类）。成功将提供第一个 β-内酰胺/BLI 产品组合，涵盖表达所有类型 β-内酰胺酶的肠杆菌科细菌。这样的产品将极大地增强临床医生在普通病房和 ICU 中对抗多重耐药革兰氏阴性病原体的装备。