Engström Patrik, Krishnan K Syam, Ngyuen Bidong D, Chorell Erik, Normark Johan, Silver Jim, Bastidas Robert J, Welch Matthew D, Hultgren Scott J, Wolf-Watz Hans, Valdivia Raphael H, Almqvist Fredrik, Bergström Sven
Department of Molecular Biology, Umeå University, Umeå, Sweden Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University, Umeå, Sweden Umeå Centre for Microbial Research (UCMR), Umeå University, Umeå, Sweden Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California, USA.
Umeå Centre for Microbial Research (UCMR), Umeå University, Umeå, Sweden Department of Chemistry, Umeå University, Umeå, Sweden.
mBio. 2014 Dec 30;6(1):e02304-14. doi: 10.1128/mBio.02304-14.
In a screen for compounds that inhibit infectivity of the obligate intracellular pathogen Chlamydia trachomatis, we identified the 2-pyridone amide KSK120. A fluorescent KSK120 analogue was synthesized and observed to be associated with the C. trachomatis surface, suggesting that its target is bacterial. We isolated KSK120-resistant strains and determined that several resistance mutations are in genes that affect the uptake and use of glucose-6-phosphate (G-6P). Consistent with an effect on G-6P metabolism, treatment with KSK120 blocked glycogen accumulation. Interestingly, KSK120 did not affect Escherichia coli or the host cell. Thus, 2-pyridone amides may represent a class of drugs that can specifically inhibit C. trachomatis infection.
Chlamydia trachomatis is a bacterial pathogen of humans that causes a common sexually transmitted disease as well as eye infections. It grows only inside cells of its host organism, within a parasitophorous vacuole termed the inclusion. Little is known, however, about what bacterial components and processes are important for C. trachomatis cellular infectivity. Here, by using a visual screen for compounds that affect bacterial distribution within the chlamydial inclusion, we identified the inhibitor KSK120. As hypothesized, the altered bacterial distribution induced by KSK120 correlated with a block in C. trachomatis infectivity. Our data suggest that the compound targets the glucose-6-phosphate (G-6P) metabolism pathway of C. trachomatis, supporting previous indications that G-6P metabolism is critical for C. trachomatis infectivity. Thus, KSK120 may be a useful tool to study chlamydial glucose metabolism and has the potential to be used in the treatment of C. trachomatis infections.
在对抑制专性胞内病原体沙眼衣原体感染性的化合物进行筛选时，我们鉴定出了2-吡啶酮酰胺KSK120。合成了一种荧光KSK120类似物，并观察到它与沙眼衣原体表面相关联，这表明其靶点是细菌。我们分离出了对KSK120耐药的菌株，并确定几个耐药突变存在于影响6-磷酸葡萄糖（G-6P）摄取和利用的基因中。与对G-6P代谢的影响一致，用KSK120处理可阻断糖原积累。有趣的是，KSK120对大肠杆菌或宿主细胞没有影响。因此，2-吡啶酮酰胺可能代表一类能够特异性抑制沙眼衣原体感染的药物。
沙眼衣原体是一种人类细菌病原体，可导致常见的性传播疾病以及眼部感染。它仅在其宿主生物体的细胞内生长，位于一个称为包涵体的寄生泡内。然而，对于沙眼衣原体细胞感染性而言，哪些细菌成分和过程很重要，人们知之甚少。在这里，通过对影响沙眼衣原体包涵体内细菌分布的化合物进行视觉筛选，我们鉴定出了抑制剂KSK120。如所假设的那样，KSK120诱导的细菌分布改变与沙眼衣原体感染性的阻断相关。我们的数据表明，该化合物靶向沙眼衣原体的6-磷酸葡萄糖（G-6P）代谢途径，支持了先前关于G-6P代谢对沙眼衣原体感染性至关重要的迹象。因此，KSK120可能是研究沙眼衣原体葡萄糖代谢的有用工具，并且有潜力用于治疗沙眼衣原体感染。
