Identification of a Host-Targeted Compound to Control Typhoid Fever.
Identification of a Host-Targeted Compound to Control Typhoid Fever.
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DOI：
10.1128/spectrum.00619-22
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发表时间：
2022-06-29
影响因子：
3.7
通讯作者：
Gunn, John S.
中科院分区：
文献类型：
--
作者：
Hoang, Ky V.;Woolard, Katherine;Yang, Ching;Melander, Christian;Gunn, John S.
伤寒主要由肠道微生物伤寒沙门氏菌引起，并且仍然是一个主要的全球健康问题，每年约有1400万新感染和136，000例死亡。虽然有抗生素可用于治疗该疾病，但全球多药耐药菌株的增加需要替代治疗方案。宿主靶向治疗提供了一种针对细胞内细菌病原体的有希望的抗感染策略。基于细胞的测定鉴定了抑制感染细胞中沙门氏菌增殖的化合物2-（3-羟丙基）-1-（3-苯氧基苯基）-1，2-二氢苯并吡喃并[2，3-c]吡咯-3，9-二酮（KH-1），其对沙门氏菌没有直接活性。该化合物抑制巨噬细胞内对抗生素敏感和耐药的沙门氏菌菌株的生长，并减少沙门氏菌感染细胞的乳酸脱氢酶（LDH）释放。随后对KH-1商业类似物的筛选鉴定出了2-（4-氟苄基）-1-（3-苯氧苯基）-1，2-二氢色烯并[2，3-c]吡咯-3，9-二酮（KH-1-2），它在控制巨噬细胞内沙门氏菌生长方面更有效。沙门氏菌感染的体外KH-1-2治疗导致感染的巨噬细胞中的细菌负荷减少8至10倍。与次优环丙沙星治疗组合，KH-1-2进一步减少巨噬细胞内的沙门氏菌生长。使用伤寒小鼠模型在体内检查KH-1-2在控制沙门氏菌感染中的毒性和功效。从用KH-1-2腹膜内处理的未感染小鼠中未观察到显著的化合物相关临床体征和肝、脾或肾的组织学发现。KH-1-2显着保护小鼠免受致死剂量的耐药沙门氏菌感染。因此，我们的研究提供了支持，这是一个有前途的先导化合物，用于开发一种新的宿主靶向治疗剂，以控制伤寒。沙门氏菌属在世界范围内造成严重的发病率和死亡率。伤寒属(e.g., S.伤寒）引起全身性疾病，通常用抗生素治疗。然而，日益增长的抗生素耐药性导致治疗失败的增加。我们筛选了化合物文库，以寻找那些能够降低沙门氏菌诱导的巨噬细胞毒性的化合物，鉴定出化合物KH-1。KH-1对细菌没有直接影响，但限制了沙门氏菌在巨噬细胞中的存活，并在伤寒小鼠模型中保护免受致命感染。次优浓度的环丙沙星与该化合物一起作用，以进一步降低沙门氏菌在巨噬细胞中的存活。一个类似物（KH-1-2）被确定为具有增加的活性，在体外巨噬细胞和在体内对两个抗生素敏感和耐药菌株。因此，我们报告了一种先导化合物的鉴定，该化合物可能是一种有用的支架，作为针对伤寒的宿主抗菌剂。
Typhoid fever is caused primarily by the enteric microbe Salmonella enterica serovar Typhi and remains a major global health problem with approximately 14 million new infections and 136,000 fatalities annually. While there are antibiotic options available to treat the disease, the global increase in multidrug-resistant strains necessitates alternative therapeutic options. Host-targeted therapeutics present a promising anti-infective strategy against intracellular bacterial pathogens. A cell-based assay identified a compound that inhibits Salmonella proliferation in infected cells, 2-(3-hydroxypropyl)-1-(3-phenoxyphenyl)-1,2-dihydrochromeno[2,3-c]pyrrole-3,9-dione (KH-1), which is devoid of direct activity against Salmonella. The compound inhibits the growth of both antibiotic-sensitive and -resistant Salmonella strains inside macrophages and reduces lactate dehydrogenase (LDH) release from Salmonella-infected cells. Subsequent screening of KH-1 commercial analogs identified 2-(4-fluorobenzyl)-1-(3-phenoxyphenyl)-1,2-dihydrochromeno[2,3-c] pyrrole-3,9-dione (KH-1-2), which is more effective in controlling Salmonella growth inside macrophages. In vitro KH-1-2 treatment of Salmonella infection resulted in an 8- to 10-fold reduction in bacterial load in infected macrophages. In combination with suboptimal ciprofloxacin treatment, KH-1-2 further reduces Salmonella growth inside macrophages. The toxicity and efficacy of KH-1-2 in controlling Salmonella infection were examined in vivo using a mouse model of typhoid fever. No significant compound-related clinical signs and histological findings of the liver, spleen, or kidney were observed from uninfected mice that were intraperitoneally treated with KH-1-2. KH-1-2 significantly protected mice from a lethal dose of infection by an antibiotic-resistant Salmonella strain. Thus, our study provides support that this is a promising lead compound for the development of a novel host-targeted therapeutic agent to control typhoid fever. IMPORTANCE Salmonella spp. cause significant morbidity and mortality worldwide. Typhoidal spp. (e.g., S. Typhi) cause a systemic disease typically treated with antibiotics. However, growing antibiotic resistance is resulting in increased treatment failures. We screened a compound library for those that would reduce Salmonella-induced macrophage toxicity, identifying compound KH-1. KH-1 has no direct effects on the bacteria but limits Salmonella survival in macrophages and protects against lethal infection in a mouse model of typhoid fever. A suboptimal concentration of ciprofloxacin worked in conjunction with the compound to further decrease Salmonella survival in macrophages. An analog (KH-1-2) was identified that possessed increased activity in vitro in macrophages and in vivo against both antibiotic-sensitive and -resistant strains. Thus, we report the identification of a lead compound that may be a useful scaffold as a host-directed antimicrobial against typhoid fever.
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影响因子：
3.8
作者：
Cruz DJ;Bonotto RM;Gomes RG;da Silva CT;Taniguchi JB;No JH;Lombardot B;Schwartz O;Hansen MA;Freitas-Junior LH
通讯作者：
Freitas-Junior LH
通过阻断 QseC，鼠伤寒沙门氏菌感染的巨噬细胞的焦亡被抑制，并促进巨噬细胞内细菌的清除
影响因子：
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作者：
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通讯作者：
Luo X
影响因子：
4.2
作者：
Moore, Terry W.;Sana, Kasinath;Yan, Dan;Krumm, Stefanie A.;Thepchatri, Pahk;Snyder, James P.;Marengo, Jose;Arrendale, Richard F.;Prussia, Andrew J.;Natchus, Michael G.;Liotta, Dennis C.;Plemper, Richard K.;Sun, Aiming
通讯作者：
Sun, Aiming
沙门氏菌效应蛋白 SopD 以 Rab8 为靶标，正向和负向调节炎症反应
影响因子：
28.3
作者：
Lian H;Jiang K;Tong M;Chen Z;Liu X;Galán JE;Gao X
通讯作者：
Gao X
DOI：
10.1016/j.jmii.2020.02.008
发表时间：
2021-08-20
影响因子：
7.4
作者：
Lin, Hsin-Hung;Chen, Hsiu-Ling;Chiu, Cheng-Hsun
通讯作者：
Chiu, Cheng-Hsun