Targeted development and selective delivery of small molecule antibiotics for the treatment of multidrug resistant Pseudomonas aeruginosa infections

用于治疗多重耐药铜绿假单胞菌感染的小分子抗生素的靶向开发和选择性递送

• 批准号: 10279394
• 负责人: Amanda Lynn Wolfe
• 金额: $ 38.44万
• 依托单位: UNIVERSITY OF NORTH CAROLINA ASHEVILLE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10279394
• 关键词: Adjuvant; Amidines; Amino Acids; Aminoglycosides; Anti-Bacterial Agents; Antibiotic Therapy; Antibiotics; Bacteria; Bacterial Infections; Binding Sites; Biochemistry; Cell Size; Cell Wall; Cell physiology; Cells; Centers for Disease Control and Prevention (U.S.); Cephalosporins; Cessation of life; Charge; Clinical; Complement; Coupled; DNA; Development; Diffusion; Divalent Cations; Drug Delivery Systems; Drug Design; Ensure; FDA approved; Fluoroquinolones; Goals; Gram-Negative Bacteria; Health; Health Care Costs; Human; Hybrids; Infection; Lead; Life; Link; Lipopolysaccharides; Membrane; Methods; Microbial Biofilms; Modification; Multi-Drug Resistance; Mycobacterium tuberculosis; Nosocomial Infections; Organic Synthesis; Outcome; Penetration; Pentamidine; Pharmacologic Substance; Polymyxins; Prodrugs; Program Development; Protein Synthesis Inhibition; Proteins; Pseudomonas aeruginosa; Pseudomonas aeruginosa infection; Public Health; Quinolones; RNA Synthesis Inhibition; Research Personnel; Resistance; Role; Scientist; Structure; System; Techniques; Time; Training; VDAC1 gene; Work; analog; bacterial resistance; beta-Lactams; cellular targeting; combat; design; drug discovery; efflux pump; improved; ineffective therapies; inhibitor/antagonist; insight; multidrug-resistant Pseudomonas aeruginosa; novel; pathogen; periplasm; research and development; resistance mechanism; small molecule; theories; trend; tuberculosis drugs; undergraduate student; uptake

PROJECT SUMMARY The continued rise in the number multidrug resistant (MDR) bacterial infections, especially those caused by Gram-negative pathogens, coupled with the dearth of novel antibiotics being FDA approved in the past 3 decades has led to a dire situation that could result in millions of deaths per year worldwide if current trends continue. MDR Pseudomonas aeruginosa (PA), a Gram-negative bacterium, is one of leading causes of nosocomial infections and has been designated as a “Serious Threat” by the CDC due to lack of viable treatment options. Two barriers that must be overcome when treating MDRPA infections are wide-spread resistance to currently prescribed antibiotics with similar mechanisms of action and poor accumulation of the antibiotic in the cell due to its additional outer membrane (OM) and promiscuous efflux pumps. Therefore, antibiotics that target unexplored cellular targets in MDRPA and methods for improved antibiotic delivery to those targets must be developed. This work proposes to first probe ATP synthase, an essential protein for all life, as an underexplored target for antibiotic development by modifying the known anti-tubercular drug bedaquiline. By comparing residue differences in the BDQ binding site between Mycobacterium tuberculosis and PA, bedaquiline-like molecules capable of inhibiting PA ATP synthase selectively will be designed. This work will also give insight into the role of ATP synthase inhibition in antibiotic drug discovery. Next, a cleavable adjuvant-antibiotic hybrid strategy will be developed to overcome the OM penetration problem in PA. The OM is made up of an asymmetric bilayer of lipopolysaccharides, porins, and substrate channels, which severely limits small molecule entry into the cell by size and charge. It has been recently demonstrated that polycationic molecules, such as aminoglycosides and bisamidines, are able to cross the OM by self-promoted uptake and are able to act as adjuvants to promote the uptake of other antibiotics. A cleavable bisamidine-antibiotic drug delivery system will be synthesized that capitalizes on the synthetic bisamidine being able to promote diffusion of the tethered antibiotic across the OM and the antibiotic being released upon enzymatic linker cleavage in the periplasm. Using a covalent but cleavable linker system ensures cellular uptake of the antibiotic without reducing antibiotic activity once in the cell. The work proposed herein will not only produce new and highly efficacious small molecules to treat MDRPA infections, it will also develop a robust and modifiable method for delivering a wide variety of antibiotics that cannot cross the OM on their own to the interior of the cell. This will ultimately increase the number of antibiotics capable of treating these infections and help to combat the growing number of resistant bacteria clinically.

项目摘要 多药耐药（MDR）细菌感染的数量持续上升，特别是由 革兰氏阴性病原体，加上缺乏新的抗生素被FDA批准在过去的30年 导致了可怕的局面，如果目前的趋势继续下去，每年可能导致全球数百万人死亡。 耐多药铜绿假单胞菌（PA）是一种革兰氏阴性菌，是引起医院感染的主要原因之一， 由于缺乏可行的治疗方案，疾病预防控制中心已将其指定为“严重威胁”。 在治疗MDRPA感染时必须克服的两个障碍是对当前MDRPA感染的广泛耐药性。 处方抗生素具有相似的作用机制，并且由于抗生素在细胞中的累积较差， 其额外的外膜（OM）和混杂的外排泵。因此，针对 MDRPA中未探索的细胞靶点和改善抗生素递送至这些靶点的方法必须 开发这项工作建议首先探测ATP合酶，一种所有生命必需的蛋白质，作为一种未被探索的蛋白质。 通过对已知的抗结核药物贝达喹啉进行修饰，成为抗生素开发的靶点。通过比较残留物 结核分枝杆菌与PA、贝达喹啉类分子BDQ结合位点的差异 将设计能够选择性抑制PA ATP合酶的药物。这项工作还将使人们深入了解 ATP合成酶抑制在抗生素药物发现中的应用。接下来，可裂解的抗菌剂-抗生素混合策略将 以克服PA中OM渗透问题。OM由以下不对称双层组成： 脂多糖、孔蛋白和底物通道，它们严重限制了小分子进入细胞， 大小和收费。最近已经证明，聚阳离子分子，如氨基糖苷类和 双脒能够通过自促进摄取穿过OM，并且能够充当佐剂以促进OM的吸收。 服用其他抗生素。将合成可裂解的双脒-抗生素药物递送系统， 利用合成的双脒能够促进栓系抗生素穿过OM的扩散 并且所述抗生素在周质中的酶促接头裂解时释放。使用共价但可裂解的 接头系统确保抗生素的细胞摄取，而不会降低一旦进入细胞的抗生素活性。的 本文提出的工作不仅将产生新的和高度有效的小分子来治疗MDRPA 它还将开发一种强大的和可修改的方法来提供各种各样的抗生素， 无法自行穿过OM到达细胞内部。这将最终增加抗生素的数量 能够治疗这些感染，并有助于在临床上对抗越来越多的耐药细菌。

项目成果

Amine Basicity of Quinoline ATP Synthase Inhibitors Drives Antibacterial Activity against Pseudomonas aeruginosa.

• DOI: 10.1021/acsmedchemlett.3c00480
• 发表时间: 2024-01-11
• 期刊: ACS MEDICINAL CHEMISTRY LETTERS
• 影响因子: 4.2
• 作者: Ward, Katie T.;Williams, Alexander P. L.;Blair, Courtney A.;Chatterjee, Ananya M.;Karthikeyan, Abirami;Roper, Addison S.;Kellogg, Casey N.;Steed, P. Ryan;Wolfe, Amanda L.
• 通讯作者: Wolfe, Amanda L.

Bisbenzamidine and Bisbenzguanidine Ureas Act as Antibacterial Agents against Pseudomonas aeruginosa.

双苯甲脒和双苯胍脲可作为针对铜绿假单胞菌的抗菌剂。

• DOI: 10.1002/cmdc.202300496
• 发表时间: 2023
• 期刊: ChemMedChem
• 影响因子: 3.4
• 作者: Kellogg,CaseyN;Pugh,BryceA;Starr,IsaakM;Parmar,DhruviJ;Troxler,A'ZaneD;Wolfe,AmandaL
• 通讯作者: Wolfe,AmandaL

Quinoline Compounds Targeting the c-Ring of ATP Synthase Inhibit Drug-Resistant Pseudomonas aeruginosa.

• DOI: 10.1021/acsinfecdis.3c00317
• 发表时间: 2023-12-08
• 期刊: ACS infectious diseases
• 影响因子: 5.3
• 作者: Fraunfelter VM;Pugh BA;Williams APL;Ward KT;Jackson DO;Austin M;Ciprich JF;Dippy L;Dunford J;Edwards GN;Glass E;Handy KM;Kellogg CN;Llewellyn K;Nyberg KQ;Shepard SJ;Thomas C;Wolfe AL;Steed PR
• 通讯作者: Steed PR

Synthesis and Evaluation of Pseudomonas aeruginosa ATP Synthase Inhibitors.

• DOI: 10.1021/acsomega.2c03127
• 发表时间: 2022-08-16
• 期刊: ACS OMEGA
• 影响因子: 4.1
• 作者: Ciprich, John F.;Buckhalt, Alexander J. E.;Carroll, Lane L.;Chen, David;DeFiglia, Steven A.;McConnell, Riley S.;Parmar, Dhruvi J.;Pistor, Olivia L.;Rao, Aliyah B.;Rubin, M. Lillian;Volk, Grace E.;Steed, P. Ryan;Wolfe, Amanda L.
• 通讯作者: Wolfe, Amanda L.

Generating Publishable Data from Course-Based Undergraduate Research Experiences in Chemistry.

• DOI: 10.1021/acs.jchemed.3c00354
• 发表时间: 2023-09-12
• 期刊: Journal of chemical education
• 影响因子: 3
• 作者: Wolfe AL;Steed PR
• 通讯作者: Steed PR