·推荐论文摘要·

抗革兰阴性细菌感染抗生素的研发新进展

徐泽奇，徐泽宇

·推荐论文摘要·

抗革兰阴性细菌感染抗生素的研发新进展

徐泽奇，徐泽宇

多药耐药（MDR）的细菌感染，尤其是MDR革兰阴性细菌感染，已经成为全球公共健康最大的威胁之一。然而，新型有效的抗生素研发并没有伴随MDR细菌的增加而增加。数十年来，新批准的抗生素数量在不断减少，治疗MDR革兰阴性细菌感染的抗生素研发在半个多世纪以来更是一直停滞不前。因此，从市场和国民生活安全的角度考虑，对新型抗生素研发的需求就显得非常迫切。虽然目前有一些化合物在体外测试、或在动物模型、甚至在临床研究中显示出一定的活性，但距离批准全面临床应用还较远。所以，全球新型的抗革兰阴性细菌感染的抗生素的供应并不乐观。本文总结了最近几年来国内外针对革兰阴性细菌感染，特别是那些已进入临床试验阶段抗生素的研发进展。除了现有抗生素的衍生物，更希望能引起对与传统抗生素作用机制不同的杀菌剂的关注。

多药耐药；革兰阴性细菌；超级细菌；抗生素；新型靶标和作用机制

来源出版物：药学学报, 2013, 487(993): 993-1004

金黄色葡萄球菌重要毒力因子的功能及其抑制剂研究进展

陈菲菲，狄红霞，蓝乐夫

摘要：金黄色葡萄球菌是重要的人类病原菌，可引起局部感染甚至致死性的全身感染，临床危害严重。广谱抗生素的使用及滥用催生并富集了包括耐甲氧西林金黄色葡萄球菌（MRSA）在内的“超级细菌”。随着“后抗生素时代”的到来，新的抗细菌感染药物的研究迫在眉睫。抗毒力药物（anti-virulence drugs）可选择性地遏制目标菌的毒素表达、细菌黏附和免疫逃避等，有望预防和治疗多种感染疾病。本文综述了抗金黄色葡萄球菌致病力的潜在药物作用靶点以及利用小分子化合物对金黄色葡萄球菌致病力进行抑制的主要研究进展。

关键词：金黄色葡萄球菌；抗生素耐药；毒力因子；小分子抑制剂

来源出版物：科学通报, 2013, 58(36): 3743-3752

人艰难梭菌感染的致病机制与防治策略研究进展

尹业师，王欣

摘要：艰难梭菌是一种非常重要的医院感染病原菌，其感染占抗菌素相关腹泻的10%～25%，占抗菌素相关肠炎的50%～75%，占抗菌素相关伪膜炎的90%～100%。而且越来越多的证据表明艰难梭菌的感染与其它疾病，如活性关节炎、婴儿突发性死亡、溶血性尿毒症、坏死性肠炎、希施斯普龙病等有关。更糟糕的是艰难梭菌存在着复发性感染，15%～20%的病人在成功治愈后会复发。近年来，随着强毒株的出现，艰难梭菌的感染率和发病率逐年上升，病情也越来越严重，由艰难梭菌感染引起的死亡率也成倍增加。到目前为止，艰难梭菌发病率升高的原因及其致病机制还有待进一步研究。由于艰难梭菌是一种孢子产生菌，对大部分抗菌素都有抗性，目前用于艰难梭菌防治的主要抗菌素甲硝唑和万古霉素的治疗效果也在不断下降，所以正确认识艰难梭菌的感染与流行，进一步了解其致病机制，寻找新的替代疗法已是迫在眉睫。本文对艰难梭菌感染和流行的病因进行了较为全面的分析，对其致病机制进行了深入的总结，并探讨了艰难梭菌防治的最新策略和方法，将有利于更好的认识和研究艰难梭菌，为艰难梭菌的防治提供新思路。

关键词：艰难梭菌；致病机制；防治

来源出版物：现代生物医学进展, 2013, 26(13): 5154-5158

噬菌体疗法在耐药性细菌感染中应用的研究进展

李菁华，孙延波

摘要：细菌耐药性已成为全球性的公共卫生问题，特别是“超级细菌”成员的不断增加使针对细菌感染的抗生素疗法面临前所未有的挑战。最近，噬菌体疗法重新受到人们的关注，并取得一些重要研究进展。本文作者就早期噬菌体的研究情况、近年来噬菌体疗法在动物实验中的应用、临床试验的最新实例和噬菌体疗法的优势及局限进行综述。

关键词：噬菌体；噬菌体疗法；细菌耐药

来源出版物：吉林大学学报（医学版）, 2013, 39(3): 630-633

6株超级细菌NDM-1基因环境研究

程灿灿，芮勇宇

摘要：目的：研究6株超级细菌NDM-1基因环境，探讨耐药基因水平转移机制。方法：收集耐碳青霉烯的G-杆菌400株，利用PCR方法检测NDM-1基因，并测序验证。根据目前报道的 NDM-1基因环境常见类型设计系列引物，步移法特异性扩增 NDM-1基因上下游序列，并对扩增产物测序和序列分析。步移法检测阴性的菌株进行全基因组HindⅢ酶切，将NDM-1基因及基因环境克隆到pET28a质粒后再测序。结果：400株对碳青霉烯类耐药的G-杆菌中有6株NDM-1阳性。步移法检出其中5株菌的基因环境，包括不动杆菌基因种13TU、产酸克雷伯菌、不动杆菌基因种 3、肺炎克雷伯菌和阴沟肠杆菌。这5株菌的基因环境与文献报道基本一致。产气肠杆菌的 NDM-1基因环境经 DNA克隆测序获得，从上游至下游为：部分缺失的转座酶Tn3、IS26及ISAbal25，blaNDM-1，ble，部分缺失的异构酶trpF和SSen4元件。结论：NDM-1基因上下游常包含转座子或插入序列等元件，为其水平转移奠定基础。

关键词：超级细菌；NDM-1；基因环境

来源出版物：实用医学杂志, 2013, 20(3): 624-634

携带NDM-1阴沟肠杆菌尿路感染株临床特点回顾性报告

曹丽军，杨靖，耿凤珍，等

摘要：目的：对 2012年 7月分离自住院患者尿液标本携带 NDM-1阴沟肠杆菌的临床特点、检测过程进行回顾性分析，探讨其耐药特征及产生机制，对控制“超级细菌”的流行提出意见。方法：依照 CLSI标准，采用K-B法和MIC法检测耐药性，改良Hodge试验和金属酶试验检测产酶类型，聚合酶链反应（PCR）检测耐药基因并进行测序。结果：此株阴沟肠杆菌对亚胺培南和美罗培南等 15种 7个类别抗生素均显示耐药，改良Hodge试验阳性，金属酶表型初筛试验阳性，经基因扩增并测序后，与Genebank比对，表明与NDM-1基因有99%的相似性，并经河北省CDC确证报告该菌株为携带NDM-1阴沟肠杆菌。结论：该尿路感染携带NDM-1基因金属酶的阴沟肠杆菌株，其产生可能与患者年老体差、恶性肿瘤伴长时滞留尿管并长时多次应用过多种抗生素有关，因此特别强调严格侵入性导尿及滞留时限指征、规范抗生素使用，做好重点消毒、隔离，控制多重耐药株发生。

关键词：阴沟肠杆菌；碳青霉烯类抗生素；NDM-1基因检测；回顾性报告

来源出版物：医学研究与教育, 2014, 31(1): 33-36

新型自组装纳米抗菌肽及抗菌肽药物研究

马诗怡，何道航

摘要：一些传统抗生素随着超级细菌的出现将面临着被淘汰的风险，而抗菌肽因其抗菌谱广、作用机制独特和不易导致耐药性等优点，有望成为理想的抗生素替代药物。近年来,随着肽自组装纳米技术的迅速发展，已有多种新型自组装纳米抗菌肽相继被设计和制备出来，并具有显著的体内外抗菌活性，展示出其作为新型安全高效抗菌药物的独特优势。新型自组装纳米抗菌肽药物的设计与研究正成为当前国际前沿热点，本文就新型自组装纳米抗菌肽及抗菌肽药物临床试验的国内外研究进展作了综述。

关键词：自组装；纳米抗菌肽；两亲性；抗菌活性；临床试验

来源出版物：中国新药杂志, 2014, 23(2): 203-209

抗生素耐药性的来源与控制对策

朱永官，欧阳纬莹，吴楠，等

摘要：抗生素除了大量用于人类疾病的治疗外，还作为饲料添加剂被广泛应用于动物养殖业。微生物的抗生素耐药性就是指微生物能够在抗生素存在的情况下生长和繁殖。抗生素耐药性是环境微生物固有的，即所谓的内在抗性，但是人类大量使用抗生素带来的抗生素抗性基因的扩散和传播普遍存在，且已开始威胁到全球人群的健康。微生物对抗生素的抗性主要有3个机制：（1）抗生素的外排；（2）抗生素的降解或修饰；（3）抗生素作用位点的保护。大量研究表明，抗生素的使用和抗生素抗性的蔓延呈现良好的相关性，而且环境微生物的抗性可以通过基因横向转移向人类致病菌扩散，最终可能导致超级细菌的爆发，直接影响人类健康。为了应对全球性的抗生素抗性问题，必须加强（1）全球抗生素使用和环境排放的监管政策和管理体系；（2）建立快速和透明的抗生素耐药性监测体系，使其涵盖医院、养殖业、污水处理厂等；（3）建立抗生素药物创新基金，通过政府和企业的联合，加快新型药物的研制；同时加强知识产权保护，使新药创制走上可持续之路；（4）加强抗生素耐药性相关的基础与应用研究，包括耐药性发生和传播的生态学机制，消除和缓解耐药性发生和传播的环境技术及其系统解决方案等，包括改进污水处理厂的处理工艺，削减出水中抗性基因和抗性菌的比例；（5）加强抗生素耐药性的科普宣传,提高全社会对耐药性的认知能力，从而在源头上有效控制抗生素在农业和医疗方面的滥用及其环境污染。

关键词：城市化；抗生素；耐药性；超级细菌；环境健康

来源出版物：中国科学院院刊, 2015, 30(4): 509-516

新德里金属β内酰胺酶-1型超级细菌的研究及防控

欧尾妹，吕媛

摘要：新德里金属β内酰胺酶-1（NDM-1）属于B1亚类金属β内酰胺酶，能水解除氨曲南外的绝大多数β内酰胺类抗菌药物，其基因大多定位在质粒上，易引起水平传播。人主要是通过院内感染、个人旅行和社区获得 3种途径感染产 NDM-1细菌。实验室检测方法有表型筛查、表型确证和基因确证。本文主要从流行情况、分子生物学特点、检测方法、预防等方面对产NDM-1细菌做一综述，旨在加强对NDM-1型超级细菌的认识和防控。

关键词：超级细菌；新德里金属β内酰胺酶—1；金属β内酰胺酶；碳青霉烯类

来源出版物：中国临床药理学杂志, 2015, 31(23): 2362-2365

中国鲍曼不动杆菌感染诊治与防控专家共识解读

周华，周建英，俞云松

摘要：鲍曼不动杆菌是临床最重要的致病菌之一，其分离率、感染率、耐药性均呈上升趋势，成为全球抗感染领域的挑战，更是目前我国最重要的“超级细菌”，临床医生在鲍曼不动杆菌感染的诊断、治疗和预防控制上存在诸多困惑。为提高鲍曼不动杆菌感染诊治与防控水平，遏制我国鲍曼不动杆菌耐药性和感染流行的快速增长，2012年我国相关领域的权威专家完成了《中国鲍曼不动杆菌感染诊治与防控专家共识》（以下简称共识）。该共识总结了我国绝大多数权威专家对于鲍曼不动杆菌感染诊治与防控的宝贵经验，对我国多重耐药菌的诊治与防控做出引领和示范。共识发表后得到了国内专家的认可和好评，本文旨在介绍该共识的主要内容，就共识发表后鲍曼不动杆菌诊治方面的新进展做进一步解读。

关键词：鲍曼不动杆菌；感染性疾病；临床实践指南；共识

来源出版物：中国循证医学杂志, 2016, 16(1): 26-29

中药抗细菌耐药性的研究进展

韩飞，幸仁汇，陈琳琦，等

摘要：细菌耐药性一直是全球关注的焦点问题，随着世界范围内化学药抗生素的滥用和“超级细菌”的层出不穷，细菌耐药性对人类的危害愈发严重，且有不可抑制的趋势。在化学药抗生素相对匮乏的今天，人们把更多的目光投向了来源广泛、安全性高、毒副作用小、抗耐药机制神秘的中草药，希望能从中找到解决耐药性问题的新途径或新思路。故近年来筛选、提取、分离天然植物及中药中有效的耐药抑制剂，探讨其抗耐药性机制，已成为药学领域研究的热点。该文从细菌耐药性的作用机制，中药抗细菌耐药性的特点及优势，抗耐性的中药成分等几个方面进行了分析和总结，希望能为解决细菌耐药性问题和研发新型中药绿色抗生素提供一定的理论基础及研究思路。

关键词：细菌；耐药性；中药；绿色抗生素

来源出版物：中国中药杂志, 2016, 41(5): 813-817

浅谈超级细菌的耐药性及诊疗机制

王逸飞

摘要：2010年8月英国医学期刊《柳叶刀传染病》杂志报道，在印度、巴基斯坦发现新型“超级细菌”。随后，欧洲和亚洲也相继报道了感染病例，且传播全球。最近，在细菌群体中出现耐药基因的传播，从而再度引起了科学家们的密切关注。本文旨在总结近年来学者对于超级细菌的认识，耐药机制，诊断治疗及预防措施。

关键词：超级细菌；耐药性；机制

来源出版物：临床医药文献电子杂志, 2016, 3(40): 8087-8088

超级细菌疫苗研究进展

邹全明，石云

摘要：“超级细菌”（superbugs）是指对抗生素有超强耐药性细菌的统称。随着抗生素滥用问题日益严重，耐药细菌不断出现并呈全球化流行趋势，“超级细菌”的家族也越来越庞大，已成为引起临床感染的严重病原菌，可能面临无药可治的境地。2014年世界卫生组织发布的《抗菌素耐药：全球监测报告》显示：每年美国因感染超级耐药细菌而死亡的人数高达 6.3万人，欧盟范围内死亡人数也有 2.5万人。超级细菌每年在美国造成的死亡人数远超过感染艾滋病毒的死亡人数。若超级细菌在全球范围的扩散得不到有效遏制，由此造成的死亡人数每年可能增加 1000万人。而为应对超级细菌蔓延，到2050年，世界需要支出100万亿美元。美国政府于2015年3月27日公布了1项为期5年的国家行动计划，以应对“紧迫而严重”的细菌耐抗生素威胁。大力推动这一计划的美国总统奥巴马指出：“抗生素耐药是当今世界面临的最紧迫的公共卫生问题之一”。加速疫苗研发是对抗细菌耐药的重要举措。

关键词：超级细菌；疫苗；耐甲氧西林金黄色葡萄球菌；铜绿假单胞菌；鲍曼不动杆菌

来源出版物：第三军医大学学报, 2016, 38(7): 663-668

Microbiological effects of sublethal levels of antibiotics

Andersson, Dan I; Hughes, Diarmaid

Ribosome-targeting antibiotics and mechanisms of bacterial resistance

Wilson, Daniel N

Persisters and beyond: Mechanisms of phenotypic drug resistance and drug tolerance in bacteria

Kester, Jemila C; Fortune, Sarah M

来源出版物：Critical Reviews in Biochemistry and Molecular Biology, 2014, 49(2): 91-101

Antimicrobial metallopolymers and their bioconjugates with conventional antibiotics against multidrug-resistant bacteria

Zhang, Jiuyang; Chen, Yung Pin; Miller, Kristen P; et al.

Abstract:Bacteria are now becoming more resistant to most conventional antibiotics. Methicillin-resistant Staphylococcus aureus (MRSA), a complex of multidrugresistant Gram-positive bacterial strains, has proven especially problematic in both hospital and community settings by deactivating conventional beta-lactam antibiotics, including penicillins, cephalosporins, and carbapenems, through various mechanisms, resulting in increased mortality rates and hospitalization costs. Here we introduce a class of charged metallopolymers that exhibit synergistic effects against MRSA by efficiently inhibiting activity of beta-lactamase and effectively lysing bacterial cells. Various conventional beta-lactam antibiotics, including penicillin-G, amoxicillin, ampicillin, and cefazolin, are protected from beta-lactamase hydrolysis via the formation of unique ion-pairs between their carboxylate anions and cationic cobaltocenium moieties. These discoveries could provide a new pathway for designing macromolecular scaffolds to regenerate vitality of conventional antibiotics to kill multidrug-resistant bacteria and superbugs.

来源出版物：Journal of the American Chemical Society, 2014, 136(13): 4873-4876

Teaching ‘old’ polymyxins new tricks: New-generation lipopeptides targeting gram-negative ‘Superbugs’

Velkov, Tony; Roberts, Kade D; Nation, Roger L; et al.

Abstract: The antimicrobial lipopeptides polymyxin B and E (colistin) are being used as a ‘last-line’ therapy for infections caused by multidrug-resistant Gram-negative pathogens. Polymyxin resistance implies a total lack of antibiotics for the treatment of life-threatening infections caused by the Gram-negative ‘superbugs’. This report details the structure-activity relationships (SAR) based design, in toto synthesis, and preclinical evaluation of a series of novel polymyxin lipopeptides with better antibacterial activity against polymyxin-resistant Gram-negative bacteria.

来源出版物：ACS Chemical Biology, 2014, 9(5): 1172-1177

Superbugs on duodenoscopes: The challenge of cleaning and disinfection of reusable devices

Humphries, Romney M; McDonnell, Gerald

Abstract: Inadequate flexible endoscope reprocessing has been associated with infection outbreaks, most recently caused by carbapenem-resistant Enterobacteriaceae. Lapsesin essential device reprocessing steps such as cleaning, disinfection/sterilization, and storage have been reported, but some outbreaks have occurred despite claimed adherence to established guidelines. Recommended changes in these guidelines include the use of sterilization instead of high-level disinfection or the use of routine microbial culturing to monitor efficacy of reprocessing. This review describes the current standards for endoscope reprocessing, associated outbreaks, and the complexities associated with both microbiological culture and sterilization approaches to mitigating the risk of infection associated with endoscopy.

来源出版物：Journal of Clinical Microbiology, 2015, 53(10):3118-3125

Identification of super antibiotic-resistant bacteria in diverse soils

Zhang, Qichun; Hou, Changping; Shamsi, Imran Haider; et al.

Abstract: Environmental bacteria have been revealed to be a reservoir of antibiotic resistance genes and a potential pool of novel resistance genes in clinical pathogens. Recently, the soils, which have never been treated with antibiotics before have proved to contain the resistant bacterial strains. In this study, we assessed whether the soil that had not previously been influenced by antibiotics contained super-resistant bacteria or not. We identified super penicillin-resistant strains in four diverse soils containing up to 1000 mg/L penicillin compared to 100 mg/L, but none of super tetracycline resistant strains were detected in four soils containing up to 1000 mg/L tetracycline, which is the highest concentration of exogenous penicillin or tetracycline reported to date. Twenty bacterial isolates were selected, representing a diverse set of species in the genera Pseudomonas (85%) and Variovorax (15%); these bacteria showed multiple antibiotic resistance patterns for four or more antibiotics. Using polymerase chain reaction and sequence, we carefully examined the existence of antibiotic-resistance genes and integron genes in soils and strains. It was observed that the resistance genes tet(C) and blaTEM were fairly widely distributed in these super penicillin-resistant isolates, and 20%-50% of tested genes were found in the study soils. All the study sites provided great opportunities for horizontal resistance transfer. The antibiotic-resistant genes pool, which is potentially large and diverse, may have considerable implications for ecology and health.

Keywords: Antibiotic-resistant genes; Multiple antibiotic resistance; Penicillin; Soil-resistant bacteria

来源出版物：International Journal of Agriculture and Biology, 2015,17(6): 1133-1140

Antimicrobial resistance investigation on Staphylococcus strains in a local hospital in Guangzhou, China, 2001-2010

Deng, Yang; Liu, Junyan; Peters, Brian M; et al.

Abstract: A retrospective study was conducted on 1739 Staphylococcus isolates from the First Affiliated Hospital of Jinan University (FAHJU) in Guangzhou during 2001-2010. With the exception of teicoplanin and vancomycin, antimicrobial resistance was commonly observed among the isolates examined, with high resistance rates for betalactamases (94.0% and 73.7% for penicillin and oxacillin) and resistance percentages for cefoxitin, chloramphenicol, ciprofloxacin, clindamycin, erythromycin, gentamicin, trimethoprim-sulfamethoxazole, and tetracycline ranging from 83.9% to 19.4%. Two hundred sixty-three of the 1,739 isolates were subjected to SCCmec typing and 42 to MLST, spaA, and coa typing. ST239-MRSA-III was prevalently identified along with one distinct coa type HIJKL and 2 spaA types (WGKAOMQ-t037 and WGKAQQ-t030). Class 1 integrons were commonly detected (31.6%), although none of the integron-positive MRSA strains had been isolated since 2009. The widespread detection of integron-based antimicrobial resistance determinants may further contribute to the emergence of superbugs.

来源出版物：Microbial Drug Resistance, 2015, 21(1): 102-104

Polymyxins: A new hope in combating Gram-negative superbugs?

Velkov, Tony; Roberts, Kade D; Thompson, Philip E; et al.

Abstract:Polymyxins have emerged as an important last-line of defense against Gram-negative ‘superbugs’. Unfortunately, the effective use of polymyxins in the clinic has been hampered by their nephrotoxic side effects. Over the last 10 years various industry and academic groups across the globe have been trying to develop new polymyxins that are safer and more efficacious than thecurrently approved polymyxin B and colistin. However these drug discovery programs are yet to deliver a new and improved polymyxin drug into the clinic. In this piece we provide an overview of the current state of these polymyxin drug discovery programs from a medicinal chemistry perspective as well as some thoughts on how future drug discovery efforts may ultimately find success. Keywords: drug discovery; nephrotoxicity; polymyxins; resistance

来源出版物：Future Medicinal Chemistry, 2016, 8(10): 1017-1025 promises unprecedented capacity for 3D nanoscale imaging and chemical mapping of bacterial cells at the ultimate 3D spatial resolution using APT.

Keywords: Cell imaging; atom probe tomography; nanoscale chemical mapping; drug resistance; polymyxin

来源出版物：NANO Letters, 2016, 93: 242-253

Near-Atomic three-dimensional mapping for site-specific chemistry of ‘Superbugs’

Adineh, Vahid R.; Marceau, Ross K. W; Velkov, Tony; et al.

Abstract: Emergence of multidrug resistant Gram-negative bacteria has caused a global health crisis and last-line class of antibiotics such as polymyxins are increasingly used. The chemical composition at the cell surface plays a key role in antibiotic resistance. Unlike imaging the cellular ultrastructure with well-developed electron microscopy, the acquisition of a high resolution chemical map of the bacterial surface still remains a technological challenge. In this study, we developed an atom probe tomography (APT) analysis approach to acquire mass spectra in the pulsed-voltage mode and reconstructed the 3D chemical distribution of atoms and molecules in the subcellular domain at the near-atomic scale. Using focused ion beam (FIB) milling together with micromanipulation, site-specific samples were retrieved from a single cell of Acinetobacter baumannii prepared as needle-shaped tips with end radii less than 60 nm, followed by a nanoscale coating of silver in the order of 10 nm. The significantly elevated conductivity provided by the metallic coating enabled successful and routine field evaporation of the biological material, with all the benefits of pulsed-voltage APT. In parallel with conventional cryo-TEM imaging, our novel approach was applied to investigate polymyxinsusceptible and-resistant strains of A. baumannii after treatment of polymyxin B. Acquired atom probe mass spectra from the cell envelope revealed characteristic fragments of phosphocholine from the polymyxinsusceptible strain, but limited signals from this molecule were detected in the polymyxin-resistant strain. This study

Breaking the spell: Combating multidrug resistant‘Superbugs’

Khan, Shahper N; Khan, Asad U

Abstract: Multidrug-resistant (MDR) bacteria have become a severe threat to community wellbeing. Conventional antibiotics are getting progressively more ineffective as a consequence of resistance, making it imperative to realize improved antimicrobial options. In this review we emphasized the microorganisms primarily reported of being resistance, referred as ESKAPE pathogens (Enterococcus faeciurn, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanii, Pseudomonas aeruginosa, and Enterobacteriaceae) accentuating their capacity to “escape” from routine antimicrobial regimes. The upcoming antimicrobial agents showing great potential and can serve as alternative therapeutic options are discussed. We also provided succinct overview of two evolving technologies; specifically network pharmacology and functional genomics profiling. Furthermore, In vivo imaging techniques can provide novel targets and a real time tool for potential lead molecule assessment. The employment of such approaches at prelude of a drug development process, will enables more informed decisions on candidate drug selection and will maximize or predict therapeutic potential before clinical testing.

Keywords: multidrug-resistant; drug development; functional genomics; network pharmacology; in vivo imaging

来源出版物：Frontiers in Microbiology, 2016, 7: 174

The bacterial mobile resistome transfer network connecting the animal and human microbiomes

HU Yong-fei; YANG Xi; LI Jing; et al.

Abstract: Horizontally acquired antibiotic resistance genes (ARGs) in bacteria are highly mobile and have been ranked as principal risk resistance determinants. However, thetransfer network of the mobile resistome and the forces driving mobile ARG transfer are largely unknown. Here, we present the whole profile of the mobile resistome in 23425 bacterial genomes and explore the effects of phylogeny and ecology on the recent transfer (≥99% nucleotide identity) of mobile ARGs. We found that mobile ARGs are mainly present in four bacterial phyla and are significantly enriched in Proteobacteria. The recent mobile ARG transfer network, which comprises 703 bacterial species and 16859 species pairs, is shaped by the bacterial phylogeny, while an ecological barrier also exists, especially when interrogating bacteria colonizing different human body sites. Phylogeny is still a driving force for the transfer of mobile ARGs between farm animals and the human gut, and, interestingly, the mobile ARGs that are shared between the human and animal gut microbiomes are also harbored by diverse human pathogens. Taking these results together, we suggest that phylogeny and ecology are complementary in shaping the bacterial mobile resistome and exert synergistic effects on the development of antibiotic resistance in human pathogens.

来源出版物：Applied and Environmental Microbiology, 2016, 82(22): 6672-6681

MCR-1.3: A new MCR variant carried by an IncP plasmid in a colistin-resistant Salmonella enterica serovar Typhimurium isolated from a healthy individual

HU Xin; HU Yong-fei; LUO Ming; et al.

Abstract: In this study, we reported a novel mcr-1 gene variant, named mcr-1.3, carried by an IncP plasmid in a colistin-resistant Salmonella Typhimurium from a healthy person. Compared with mcr-1, the mcr-1.3 gene contained two SNPs; one of them resulted in an arginine to histidine variation (Arg536->His). The plasmid carrying mcr-1.3 gene was designated pMCR1.3_P053, and was highly similar to a recently discovered mcr-1-bearing plasmid found in Klebsiella pneumoniae.

来源出版物：Antimicrobial Agents and Chemotherapy (online), 2017, doi: 10.1128/AAC.02632-16

责任编辑：卫夏雯

Host-directed therapy of tuberculosis based on interleukin-1 and type I interferon crosstalk

Mayer-Barber, Katrin D; Andrade, Bruno B; Oland, Sandra D; et al.

Tuberculosis remains second only to HIV/AIDS as the leading cause of mortality worldwide due to a single infectious agent. Despite chemotherapy, the global tuberculosis epidemic has intensified because of HIV co-infection, the lack of an effective vaccine and the emergence of multi-drug-resistant bacteria. Alternative host-directed strategies could be exploited to improve treatment efficacy and outcome, contain drug-resistant strains and reduce disease severity and mortality. The innate inflammatory response elicited by Mycobacterium tuberculosis (Mtb) represents a logical host target. Here we demonstrate that interleukin-1 (IL-1) confers host resistance through the induction of eicosanoids that limit excessive type I interferon (IFN) production and foster bacterial containment. We further show that, in infected mice and patients, reduced IL-1 responses and/or excessive type I IFN induction are linked to an eicosanoid imbalance associated with disease exacerbation. Host-directed immunotherapy with clinically approved drugs that augment prostaglandin E2 levels in these settings prevented acute mortality of Mtb-infected mice. Thus, IL-1 and type I IFNs represent two major counter-regulatory classes of inflammatory cytokines that control the outcome of Mtb infection and are functionally linked via eicosanoids. Our findings establish proof of concept for host-directed treatment strategies that manipulate the host eicosanoid network and represent feasible alternatives to conventional chemotherapy.

来源出版物：Nature, 2014, 511(7507): 99-105

Abstract: The widespread use of antibiotics results in the generation of antibiotic concentration gradients in humans, livestock and the environment. Thus, bacteria are frequently exposed to non-lethal (that is, subinhibitory) concentrations of drugs, and recent evidence suggests that this is likely to have an important role in the evolution of antibiotic resistance. In this Review, we discuss the ecology of antibiotics and the ability of subinhibitory concentrations to select for bacterial resistance. We also consider the effects of low-level drug exposure on bacterial physiology, including the generation of genetic and phenotypic variability, as well as the ability of antibiotics to function as signalling molecules. Together, these effects accelerate the emergence and spread of antibiotic-resistant bacteria among humans and animals.

来源出版物：Nature Reviews Microbiology, 2014, 12(7): 465-478

Abstract:The ribosome is one of the main antibiotic targets in the bacterial cell. Crystal structures of naturally produced antibiotics and their semi-synthetic derivativesbound to ribosomal particles have provided unparalleled insight into their mechanisms of action, and they are also facilitating the design of more effective antibiotics for targeting multidrug-resistant bacteria. In this review, I discuss the recent structural insights into the mechanism of action of ribosome-targeting antibiotics and the molecular mechanisms of bacterial resistance, in addition to the approaches that are being pursued for the production of improved drugs that inhibit bacterial protein synthesis.

来源出版物：Nature Reviews Microbiology, 2014, 12(1): 35-48

Abstract: One of the challenges in clinical infectious diseases is the problem of chronic infections, which can require long durations of antibiotic treatment and often recur. An emerging explanation for the refractoriness of some infections to treatment is the existence of subpopulations of drug tolerant cells. While typically discussed as “persister” cells, it is becoming increasingly clear that there is significant heterogeneity in drug responses within a bacterial population and that multiple mechanisms underlie the emergence of drug tolerant and drug-resistant subpopulations. Many of these parallel mechanisms have been shown to affect drug susceptibility at the level of a whole population. Here we review mechanisms of phenotypic drug tolerance and resistance in bacteria with the goal of providing a framework for understanding the similarities and differences in these cells.

asymmetric growth and division; biofilm; cellular differentiation; chronic infections; efflux pumps; permeability; population heterogeneity