François Malouin , Eric Brouillette , Alejandro Martinez , Bobbi J. Boyll , James L. Toth , Jennifer L. Gage , Norris E. Allen
{"title":"抗细胞内金黄色葡萄球菌抗菌化合物的鉴定","authors":"François Malouin , Eric Brouillette , Alejandro Martinez , Bobbi J. Boyll , James L. Toth , Jennifer L. Gage , Norris E. Allen","doi":"10.1016/j.femsim.2005.04.003","DOIUrl":null,"url":null,"abstract":"<div><p>Small-colony variants (SCVs) of <span><em>Staphylococcus aureus</em></span><span><span><span> exhibit characteristics of bacteria that can penetrate mammalian cells and remain intracellular and innocuous for indefinite periods. These properties make SCVs a convenient tool that can be used to identify new antibacterial agents having activity against intracellular, quiescent bacteria. Agents active against SCVs could be useful in the treatment of chronic </span>staphylococcal infections such as bovine </span>mastitis. An </span><em>hemB</em><span> deletion mutant of </span><em>S. aureus</em> Newbould, a bovine mastitis isolate, having a stable, genetically defined SCV phenotype, was used in a screening program to identify compounds active against intracellular, gram-positive bacteria. Out of more than 260,000 compounds screened, nine compounds having the desired properties were identified. The range of MICs against gram-positive bacteria was ⩽0.12–32<!--> <!-->μg<!--> <!-->ml<sup>−1</sup>. One of the compounds (no. <strong>8</strong>) showed excellent activity against gram-positive (MICs ⩽0.12<!--> <!-->μg<!--> <!-->ml<sup>−1</sup>) and gram-negative (MICs ⩽0.12–4<!--> <!-->μg<!--> <!-->ml<sup>−1</sup>) bacteria. Each of the nine compounds demonstrated efficacy in a neutropenic mouse thigh infection model. Two compounds, including compound no. <strong>8</strong>, reduced numbers of bacteria in a mouse mastitis model of infection. Application of a stepwise screening process has identified lead compounds that may be useful for treating persistent, intracellular infections.</p></div>","PeriodicalId":12220,"journal":{"name":"FEMS immunology and medical microbiology","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2005-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.femsim.2005.04.003","citationCount":"10","resultStr":"{\"title\":\"Identification of antimicrobial compounds active against intracellular Staphylococcus aureus\",\"authors\":\"François Malouin , Eric Brouillette , Alejandro Martinez , Bobbi J. Boyll , James L. Toth , Jennifer L. Gage , Norris E. Allen\",\"doi\":\"10.1016/j.femsim.2005.04.003\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>Small-colony variants (SCVs) of <span><em>Staphylococcus aureus</em></span><span><span><span> exhibit characteristics of bacteria that can penetrate mammalian cells and remain intracellular and innocuous for indefinite periods. These properties make SCVs a convenient tool that can be used to identify new antibacterial agents having activity against intracellular, quiescent bacteria. Agents active against SCVs could be useful in the treatment of chronic </span>staphylococcal infections such as bovine </span>mastitis. An </span><em>hemB</em><span> deletion mutant of </span><em>S. aureus</em> Newbould, a bovine mastitis isolate, having a stable, genetically defined SCV phenotype, was used in a screening program to identify compounds active against intracellular, gram-positive bacteria. Out of more than 260,000 compounds screened, nine compounds having the desired properties were identified. The range of MICs against gram-positive bacteria was ⩽0.12–32<!--> <!-->μg<!--> <!-->ml<sup>−1</sup>. One of the compounds (no. <strong>8</strong>) showed excellent activity against gram-positive (MICs ⩽0.12<!--> <!-->μg<!--> <!-->ml<sup>−1</sup>) and gram-negative (MICs ⩽0.12–4<!--> <!-->μg<!--> <!-->ml<sup>−1</sup>) bacteria. Each of the nine compounds demonstrated efficacy in a neutropenic mouse thigh infection model. Two compounds, including compound no. <strong>8</strong>, reduced numbers of bacteria in a mouse mastitis model of infection. Application of a stepwise screening process has identified lead compounds that may be useful for treating persistent, intracellular infections.</p></div>\",\"PeriodicalId\":12220,\"journal\":{\"name\":\"FEMS immunology and medical microbiology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2005-08-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://sci-hub-pdf.com/10.1016/j.femsim.2005.04.003\",\"citationCount\":\"10\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"FEMS immunology and medical microbiology\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0928824405001136\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"FEMS immunology and medical microbiology","FirstCategoryId":"1085","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0928824405001136","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 10
摘要
金黄色葡萄球菌(Staphylococcus aureus)的小菌落变异(SCVs)表现出可以穿透哺乳动物细胞并在细胞内无限期保持无害的细菌特征。这些特性使scv成为一种方便的工具,可用于鉴定对细胞内静止细菌具有活性的新型抗菌剂。抗scv活性药物可用于治疗慢性葡萄球菌感染,如牛乳腺炎。金黄色葡萄球菌Newbould的hemB缺失突变体,牛乳腺炎分离物,具有稳定的,遗传定义的SCV表型,用于筛选程序,以确定对细胞内革兰氏阳性细菌有活性的化合物。在筛选的26万多个化合物中,确定了9个具有所需性质的化合物。对革兰氏阳性菌的mic作用范围为≤0.12 ~ 32 μ ml−1。其中一种化合物(no。8)对革兰氏阳性菌(mic≥0.12 μ ml - 1)和革兰氏阴性菌(mic≥0.12 - 4 μ ml - 1)具有良好的抑菌活性。九种化合物中的每一种都在中性粒细胞减少的小鼠大腿感染模型中表现出功效。两种化合物,包括化合物号。8、减少了小鼠乳腺炎感染模型中的细菌数量。应用逐步筛选过程已经确定了可能对治疗持续性细胞内感染有用的先导化合物。
Identification of antimicrobial compounds active against intracellular Staphylococcus aureus
Small-colony variants (SCVs) of Staphylococcus aureus exhibit characteristics of bacteria that can penetrate mammalian cells and remain intracellular and innocuous for indefinite periods. These properties make SCVs a convenient tool that can be used to identify new antibacterial agents having activity against intracellular, quiescent bacteria. Agents active against SCVs could be useful in the treatment of chronic staphylococcal infections such as bovine mastitis. An hemB deletion mutant of S. aureus Newbould, a bovine mastitis isolate, having a stable, genetically defined SCV phenotype, was used in a screening program to identify compounds active against intracellular, gram-positive bacteria. Out of more than 260,000 compounds screened, nine compounds having the desired properties were identified. The range of MICs against gram-positive bacteria was ⩽0.12–32 μg ml−1. One of the compounds (no. 8) showed excellent activity against gram-positive (MICs ⩽0.12 μg ml−1) and gram-negative (MICs ⩽0.12–4 μg ml−1) bacteria. Each of the nine compounds demonstrated efficacy in a neutropenic mouse thigh infection model. Two compounds, including compound no. 8, reduced numbers of bacteria in a mouse mastitis model of infection. Application of a stepwise screening process has identified lead compounds that may be useful for treating persistent, intracellular infections.