Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers University, Piscataway, New Jersey, United States of America.
The George H. Cook Undergraduate Honors Scholars Program, School of Environmental and Biological Sciences, Rutgers University, New Brunswick, New Jersey, United States of America.
PLoS One. 2019 Mar 1;14(3):e0212874. doi: 10.1371/journal.pone.0212874. eCollection 2019.
Chlamydia is a common pathogen that can causes serious complications in the reproductive system and eyes. Lack of vaccine and other effective prophylactic measures coupled with the largely asymptomatic nature and unrare clinical treatment failure calls for development of new antichlamydials, particularly selective antichlamydials without adverse effects on humans and the beneficial microbiota. We previously reported that benzal-N-acylhydrazones (BAH) can inhibit chlamydiae without detectable adverse effects on host cells and beneficial lactobacilli that dominate the human vaginal microbiota among reproductive-age women. However, the antichlamydial mechanism of BAH is not known. Whereas 4 single nucleotide polymorphisms (i.e., SNP1-4) were identified in a rare Chlamydia variant with a low level of BAH resistance, termed MCR, previous studies failed to establish a causal effect of any particular SNP(s). In the present work, we performed recombination to segregate the four SNPs. Susceptibility tests indicate that the R51G GrgA allele is both necessary and sufficient for the low level of BAH resistance. Thus, the Chlamydia-specific transcription factor GrgA either is a direct target of BAH or regulates BAH susceptibility. We further confirm an extremely low rate of BAH resistance in Chlamydia. Our findings warrant exploration of GrgA as a therapeutic and prophylactic target for chlamydial infections.
衣原体是一种常见的病原体，可导致生殖系统和眼睛严重并发症。缺乏疫苗和其他有效预防措施，加上很大程度上无症状的性质和罕见的临床治疗失败，需要开发新的抗衣原体药物，特别是对人体和有益微生物群无不良影响的选择性抗衣原体药物。我们之前报道过苯甲酰-N-酰腙（BAH）可以抑制衣原体，而对宿主细胞和在育龄妇女的阴道微生物群中占主导地位的有益乳杆菌没有可检测到的不良影响。然而，BAH 的抗衣原体机制尚不清楚。虽然在一种罕见的低 BAH 耐药性的衣原体变体中鉴定出 4 个单核苷酸多态性（即 SNP1-4），但之前的研究未能确定任何特定 SNP 的因果效应。在本工作中，我们进行了重组以分离这 4 个 SNP。敏感性试验表明，R51G GrgA 等位基因对于低水平的 BAH 耐药性是必需且充分的。因此，衣原体特异性转录因子 GrgA 要么是 BAH 的直接靶标，要么调节 BAH 敏感性。我们进一步证实了衣原体中 BAH 耐药性的极低发生率。我们的发现证明了 GrgA 作为治疗和预防衣原体感染的靶点是合理的。
