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Development of a Novel Class of Multifunctional Virulence-Attenuating Antibiotics.

机译：一类新型多功能毒力减毒抗生素的研制。

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摘要

Resistance to traditional antibiotics arises largely because killing bacteria or halting their reproduction induces a selective pressure on mutants able to survive treatment. Virulence-attenuating antibiotics attempt to reduce resistance induction by instead targeting the mechanisms bacteria use to enhance survival within a host (“virulence factors”). Our collaborators in the Sun group at the University of Missouri – Columbia identified streptokinase (SK) as a virulence factor that confers Group A Streptococcus (GAS) the ability to infect human hosts. SK potently activates the human fibrinolytic enzyme plasmin, which allows GAS to evade the host’s response of clotting around sites of infection. High-throughput screening (HTS) for compounds able to attenuate GAS-SK production at the transcriptional level identified 3-allyl-2-(butylthio)-3H-spiro[benzo[h]quinazoline-5,1'-cyclohexan]-4(6H)-one as a moderately potent lead compound. Through extensive structure-activity relationship (SAR) studies, we were able to identify an analog, 3-allyl-2-(ethylthio)-9-methoxy-5,5-dimethyl-5,6-dihydrobenzo[h]quinazolin-4(3H)-one, with 35-fold higher potency (IC50 = 1.3 µM). We also identified several substitution patterns that confer enhanced metabolic stability to the molecular scaffold.In tandem with the SAR expansion effort, the identification of the macromolecular target(s) of this class of compounds was also pursued. To this end, we developed several classes of chemical probes designed to specifically interact with target protein(s), while offering a mechanism for the visualization or selective purification of the protein-probe complex. Though these probes have yet to convincingly identify a possible target, the use of more sensitive target identification assays, including quantitative proteomics and phage display, is currently being investigated.Finally, RNA microarray studies suggested that compounds from this series also inhibit biofilm formation. Biofilm-embedded colonies secrete a sticky extracellular matrix that effectively sequesters them from the immune response and antibiotic treatment. A second SAR study explored the extent to which our compounds can be used to control biofilms in the clinically-relevant Staphylococcus species. This study successfully identified a number of potent analogs, including several that exerted protective effects in murine models of S. aureus infection. One compound, 9-methoxy-3,5,5-trimethyl-2-((2,2,2-trifluoroethyl)thio)-5,6-dihydrobenzo[h]quinazolin-4(3H)-one, was found to be both reasonably active (IC50 = 3.7 µM) and metabolically stable (microsomal t1/2 = 19.6 min), increasing its potential for achieving efficacy in vivo.
机译：对传统抗生素的抗性之所以出现，主要是因为杀死细菌或停止其繁殖对能够存活的突变体产生选择性压力。降低毒力的抗生素试图通过针对细菌用来提高宿主体内存活率的机制（“毒力因子”）来减少耐药性的诱导。我们密苏里大学哥伦比亚分校Sun组的合作者确定链激酶（SK）是一种赋予A组链球菌（GAS）感染人类宿主能力的毒力因子。 SK可以有效激活人纤溶酶纤溶酶，从而使GAS能够逃避宿主在感染部位周围凝结的反应。高通量筛选（HTS）能够在转录水平上减弱GAS-SK生成的化合物鉴定为3-烯丙基-2-（丁硫基）-3H-螺[苯并[h]喹唑啉-5,1'-环己] -4 （6H）-一种中等效力的铅化合物。通过广泛的结构活性关系（SAR）研究，我们能够鉴定出类似的3-烯丙基-2-（乙硫基）-9-甲氧基-5,5-二甲基-5,6-二氢苯并[h]喹唑啉-4 （3H）-1，效能提高35倍（IC50 = 1.3 µM）。我们还确定了几种取代模式，赋予分子支架增强的代谢稳定性。与SAR扩展相结合，还寻求鉴定这类化合物的大分子靶标。为此，我们开发了几类化学探针，旨在与目标蛋白特异性相互作用，同时提供可视化或选择性纯化蛋白探针复合物的机制。尽管这些探针尚不能令人信服地鉴定出可能的靶标，但目前正在研究使用更敏感的靶标鉴定测定法，包括定量蛋白质组学和噬菌体展示。最后，RNA微阵列研究表明该系列化合物还可以抑制生物膜的形成。嵌入生物膜的菌落分泌一种粘性的细胞外基质，可有效隔离免疫应答和抗生素治疗。 SAR的第二项研究探索了我们的化合物可用于控制临床相关葡萄球菌物种中生物膜的程度。这项研究成功地鉴定了许多有效的类似物，包括在金黄色葡萄球菌感染的鼠模型中发挥保护作用的几种类似物。发现一种化合物9-甲氧基-3,5,5-三甲基-2-（（（2,2,2-三氟乙基）硫基）-5,6-二氢苯并[h]喹唑啉-4（3H）-具有合理活性（IC50 = 3.7 µM）和代谢稳定（微粒体t1 / 2 = 19.6分钟），从而增加了其在体内获得疗效的潜力。

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    Yestrepsky Bryan Daniel;

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  • 年度 2013
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