PDF(Pubmed)
Abstract：
The obligate intracellular bacterium, Chlamydia trachomatis, has evolved to depend on its human host for many metabolites, including most amino acids and three of the four nucleotides. Given this, it is not surprising that depletion of a single amino acid in the host cell growth medium blocks chlamydial replication. Paradoxically, supra-normal levels of some amino acids also block productive replication of Chlamydia. Here, we have determined how elevated serine levels, generated by exogenous supplementation, impede chlamydial inclusion development and reduce the generation of infectious progeny. Our findings reveal that human serine racemase, which is broadly expressed in multiple tissues, potentiates the anti-chlamydial effect of elevated serine concentrations. In addition to reversibly converting l-serine to d-serine, serine racemase also deaminates serine via β-elimination. We have determined that d-serine does not directly impact Chlamydia; rather, ammonia generated by serine deamination limits the productive chlamydial replication. Our findings imply that ammonia produced within host cells can traverse the chlamydial inclusion membrane. Further, this property of serine deaminase can be exploited to sensitize Chlamydia to concentrations of doxycycline that are otherwise not bactericidal. Because exogenously elevated levels of serine can be tolerated over extended periods, the broad expression pattern of serine racemase indicates it to be a host enzyme whose activity can be directed against multiple intracellular bacterial pathogens. From a therapeutic perspective, demonstrating host metabolism can be skewed to generate an anti-bacterial metabolite that synergizes with antibiotics, we believe our results provide a new approach to target intracellular pathogens.
摘要：
专性细胞内细菌，沙眼衣原体,已经进化到许多代谢物依赖于它的人类宿主，包括大多数氨基酸和四个核苷酸中的三个。鉴于此,在宿主细胞生长培养基中单个氨基酸的消耗阻断衣原体复制并不令人惊讶。矛盾的是,某些氨基酸的超常水平也会阻断衣原体的生产性复制。这里,我们已经确定了丝氨酸水平的升高，通过外源性补充产生，阻碍衣原体包涵体发育并减少感染性后代的产生。我们的发现揭示了人类丝氨酸消旋酶，在多个组织中广泛表达，增强丝氨酸浓度升高的抗衣原体作用。除了可逆地将l-丝氨酸转化为d-丝氨酸之外，丝氨酸消旋酶还通过β-消除使丝氨酸脱氨。我们已经确定d-丝氨酸不会直接影响衣原体；相反，丝氨酸脱氨产生的氨限制了衣原体的生产性复制。我们的发现暗示宿主细胞内产生的氨可以穿过衣原体包涵膜。Further,丝氨酸脱氨酶的这种特性可用于使衣原体对多西环素的浓度敏感，否则不会杀菌。因为丝氨酸水平的外源升高可以长时间耐受，丝氨酸消旋酶的广泛表达模式表明它是一种宿主酶，其活性可以针对多种细胞内细菌病原体。从治疗的角度来看，通过证明宿主代谢可以偏斜以产生与抗生素协同作用的抗菌代谢产物，我们相信我们的结果为靶向细胞内病原体提供了一种新的方法。
