Neisseria gonorrhoeae (Ng) and Chlamydia trachomatis (Ct) are the most commonly reported sexually transmitted bacteria worldwide and usually present as co-infections. Increasing resistance of Ng to currently recommended dual therapy of azithromycin and ceftriaxone presents therapeutic challenges for syndromic management of Ng-Ct co-infections. Development of a safe, effective, and inexpensive dual therapy for Ng-Ct co-infections is an effective strategy for the global control and prevention of these two most prevalent bacterial sexually transmitted infections. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a validated drug target with two approved drugs for indications other than antibacterials. Nonetheless, any new drugs targeting GAPDH in Ng and Ct must be specific inhibitors of bacterial GAPDH that do not inhibit human GAPDH, and structural information of Ng and Ct GAPDH will aid in finding such selective inhibitors. Here, we report the X-ray crystal structures of Ng and Ct GAPDH. Analysis of the structures demonstrates significant differences in amino acid residues in the active sites of human GAPDH from those of the two bacterial enzymes suggesting design of compounds to selectively inhibit Ng and Ct is possible. We also describe an efficient in vitro assay of recombinant GAPDH enzyme activity amenable to high-throughput drug screening to aid in identifying inhibitory compounds and begin to address selectivity.

中文翻译：

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淋病奈瑟菌和沙眼衣原体中甘油醛 3-磷酸脱氢酶的结构。

淋病奈瑟菌 (Ng) 和沙眼衣原体 (Ct) 是全世界最常报道的性传播细菌，通常作为共同感染存在。Ng 对目前推荐的阿奇霉素和头孢曲松双重治疗的耐药性增加，对 Ng-Ct 合并感染的综合征管理提出了治疗挑战。为 Ng-Ct 合并感染开发一种安全、有效且廉价的双重疗法是全球控制和预防这两种最普遍的细菌性传播感染的有效策略。甘油醛-3-磷酸脱氢酶 (GAPDH) 是一种经过验证的药物靶点，有两种批准的药物用于除抗菌药物以外的适应症。尽管如此，任何针对 Ng 和 Ct 中 GAPDH 的新药都必须是不抑制人类 GAPDH 的细菌 GAPDH 的特异性抑制剂，Ng 和 Ct GAPDH 的结构信息将有助于寻找此类选择性抑制剂。在这里，我们报告了 Ng 和 Ct GAPDH 的 X 射线晶体结构。结构分析表明，人类 GAPDH 活性位点的氨基酸残基与两种细菌酶的氨基酸残基存在显着差异，这表明设计化合物以选择性抑制 Ng 和 Ct 是可能的。我们还描述了一种有效的重组 GAPDH 酶活性体外测定法，适用于高通量药物筛选，以帮助识别抑制性化合物并开始解决选择性问题。结构分析表明，人类 GAPDH 活性位点的氨基酸残基与两种细菌酶的氨基酸残基存在显着差异，这表明设计化合物以选择性抑制 Ng 和 Ct 是可能的。我们还描述了一种有效的重组 GAPDH 酶活性体外测定法，适用于高通量药物筛选，以帮助识别抑制性化合物并开始解决选择性问题。结构分析表明，人类 GAPDH 活性位点的氨基酸残基与两种细菌酶的氨基酸残基存在显着差异，这表明设计化合物以选择性抑制 Ng 和 Ct 是可能的。我们还描述了一种有效的重组 GAPDH 酶活性体外测定法，适用于高通量药物筛选，以帮助识别抑制性化合物并开始解决选择性问题。