In the absence of a vaccine, multidrug-resistant Neisseria gonorrhoeae has emerged as a major human health threat, and new approaches to treat gonorrhea are urgently needed. N. gonorrhoeae pili are posttranslationally modified by a glycan that terminates in a galactose. The terminal galactose is critical for initial contact with the human cervical mucosa via an interaction with the I-domain of complement receptor 3 (CR3). We have now identified the I-domain galactose-binding epitope and characterized its galactose-specific lectin activity. Using surface plasmon resonance and cellular infection assays, we found that a peptide mimic of this galactose-binding region competitively inhibited the N. gonorrhoeae-CR3 interaction. A compound library was screened for potential drugs that could similarly prohibit the N. gonorrhoeae-CR3 interaction and be repurposed as novel host-targeted therapeutics for multidrug-resistant gonococcal infections in women. Two drugs, methyldopa and carbamazepine, prevented and cured cervical cell infection by multidrug-resistant gonococci by blocking the gonococcal-CR3 I-domain interaction.IMPORTANCE Novel therapies that avert the problem of Neisseria gonorrhoeae with acquired antibiotic resistance are urgently needed. Gonococcal infection of the human cervix is initiated by an interaction between a galactose modification made to its surface appendages, pili, and the I-domain region of (host) complement receptor 3 (CR3). By targeting this crucial gonococcal-I-domain interaction, it may be possible to prevent cervical infection in females. To this end, we identified the I-domain galactose-binding epitope of CR3 and characterized its galactose lectin activity. Moreover, we identified two drugs, carbamazepine and methyldopa, as effective host-targeted therapies for gonorrhea treatment. At doses below those currently used for their respective existing indications, both carbamazepine and methyldopa were more effective than ceftriaxone in curing cervical infection ex vivo This host-targeted approach would not be subject to N. gonorrhoeae drug resistance mechanisms. Thus, our data suggest a long-term solution to the growing problem of multidrug-resistant N. gonorrhoeae infections.

中文翻译：

---

阻断淋球菌-补体受体3相互作用的重用药物可以预防和治疗原代人宫颈上皮细胞的淋球菌感染。

在没有疫苗的情况下，耐多药性淋病奈瑟氏球菌已成为对人类健康的主要威胁，因此迫切需要治疗淋病的新方法。淋病奈瑟菌毛被终止于半乳糖的聚糖翻译后修饰。末端半乳糖对于通过与补体受体3（CR3）的I结构域的相互作用与人宫颈粘膜的初始接触至关重要。现在，我们已经确定了I结构域半乳糖结合表位，并表征了其半乳糖特异性凝集素的活性。使用表面等离振子共振和细胞感染测定法，我们发现模拟半乳糖结合区的肽竞争性抑制淋病奈瑟氏球菌-CR3相互作用。对化合物库进行了筛选，以寻找可能类似地禁止N的潜在药物。淋球菌-CR3相互作用，并被重新用作针对女性的多药耐药性淋球菌感染的新型宿主靶向疗法。甲基多巴和卡马西平这两种药物可通过阻断淋球菌-CR3 I结构域的相互作用来预防和治愈多药耐药的淋球菌对宫颈细胞的感染。重要事项迫切需要能避免淋病奈瑟氏球菌获得性耐药的新型疗法。人宫颈的淋球菌感染是由对其表面附肢，菌毛和（宿主）补体受体3（CR3）的I结构域进行的半乳糖修饰之间的相互作用引发的。通过靶向这种关键的淋球菌-I结构域相互作用，可以预防女性的宫颈感染。为此，我们确定了CR3的I域半乳糖结合表位，并表征了其半乳糖凝集素活性。此外，我们确定了卡马西平和甲基多巴这两种药物作为淋病治疗的有效宿主靶向疗法。在低于目前用于其各自现有适应症的剂量时，卡马西平和甲基多巴在体外离体治愈宫颈感染方面比头孢曲松更为有效。这种针对宿主的方法不会受到淋病奈瑟菌的耐药性机制的影响。因此，我们的数据提出了对多重耐药性淋病奈瑟氏球菌感染日益严重的问题的长期解决方案。在低于目前用于其各自现有适应症的剂量时，卡马西平和甲基多巴在体外离体治愈宫颈感染方面比头孢曲松更为有效。这种针对宿主的方法不会受到淋病奈瑟菌的耐药性机制的影响。因此，我们的数据提出了对多重耐药性淋病奈瑟氏球菌感染日益严重的问题的长期解决方案。在低于目前用于其各自现有适应症的剂量时，卡马西平和甲基多巴在体外离体治愈宫颈感染方面比头孢曲松更为有效。这种针对宿主的方法不会受到淋病奈瑟菌的耐药性机制的影响。因此，我们的数据提出了对多重耐药性淋病奈瑟氏球菌感染日益严重的问题的长期解决方案。