·推薦論文摘要·

抗革蘭陰性細菌感染抗生素的研發(fā)新進展

徐澤奇，徐澤宇

·推薦論文摘要·

抗革蘭陰性細菌感染抗生素的研發(fā)新進展

徐澤奇，徐澤宇

多藥耐藥（MDR）的細菌感染，尤其是MDR革蘭陰性細菌感染，已經(jīng)成為全球公共健康最大的威脅之一。然而，新型有效的抗生素研發(fā)并沒有伴隨MDR細菌的增加而增加。數(shù)十年來，新批準的抗生素數(shù)量在不斷減少，治療MDR革蘭陰性細菌感染的抗生素研發(fā)在半個多世紀以來更是一直停滯不前。因此，從市場和國民生活安全的角度考慮，對新型抗生素研發(fā)的需求就顯得非常迫切。雖然目前有一些化合物在體外測試、或在動物模型、甚至在臨床研究中顯示出一定的活性，但距離批準全面臨床應(yīng)用還較遠。所以，全球新型的抗革蘭陰性細菌感染的抗生素的供應(yīng)并不樂觀。本文總結(jié)了最近幾年來國內(nèi)外針對革蘭陰性細菌感染，特別是那些已進入臨床試驗階段抗生素的研發(fā)進展。除了現(xiàn)有抗生素的衍生物，更希望能引起對與傳統(tǒng)抗生素作用機制不同的殺菌劑的關(guān)注。

多藥耐藥；革蘭陰性細菌；超級細菌；抗生素；新型靶標和作用機制

來源出版物：藥學(xué)學(xué)報, 2013, 487(993): 993-1004

金黃色葡萄球菌重要毒力因子的功能及其抑制劑研究進展

陳菲菲，狄紅霞，藍樂夫

摘要：金黃色葡萄球菌是重要的人類病原菌，可引起局部感染甚至致死性的全身感染，臨床危害嚴重。廣譜抗生素的使用及濫用催生并富集了包括耐甲氧西林金黃色葡萄球菌（MRSA）在內(nèi)的“超級細菌”。隨著“后抗生素時代”的到來，新的抗細菌感染藥物的研究迫在眉睫?？苟玖λ幬铮╝nti-virulence drugs）可選擇性地遏制目標菌的毒素表達、細菌黏附和免疫逃避等，有望預(yù)防和治療多種感染疾病。本文綜述了抗金黃色葡萄球菌致病力的潛在藥物作用靶點以及利用小分子化合物對金黃色葡萄球菌致病力進行抑制的主要研究進展。

關(guān)鍵詞：金黃色葡萄球菌；抗生素耐藥；毒力因子；小分子抑制劑

來源出版物：科學(xué)通報, 2013, 58(36): 3743-3752

人艱難梭菌感染的致病機制與防治策略研究進展

尹業(yè)師，王欣

摘要：艱難梭菌是一種非常重要的醫(yī)院感染病原菌，其感染占抗菌素相關(guān)腹瀉的10%～25%，占抗菌素相關(guān)腸炎的50%～75%，占抗菌素相關(guān)偽膜炎的90%～100%。而且越來越多的證據(jù)表明艱難梭菌的感染與其它疾病，如活性關(guān)節(jié)炎、嬰兒突發(fā)性死亡、溶血性尿毒癥、壞死性腸炎、希施斯普龍病等有關(guān)。更糟糕的是艱難梭菌存在著復(fù)發(fā)性感染，15%～20%的病人在成功治愈后會復(fù)發(fā)。近年來，隨著強毒株的出現(xiàn)，艱難梭菌的感染率和發(fā)病率逐年上升，病情也越來越嚴重，由艱難梭菌感染引起的死亡率也成倍增加。到目前為止，艱難梭菌發(fā)病率升高的原因及其致病機制還有待進一步研究。由于艱難梭菌是一種孢子產(chǎn)生菌，對大部分抗菌素都有抗性，目前用于艱難梭菌防治的主要抗菌素甲硝唑和萬古霉素的治療效果也在不斷下降，所以正確認識艱難梭菌的感染與流行，進一步了解其致病機制，尋找新的替代療法已是迫在眉睫。本文對艱難梭菌感染和流行的病因進行了較為全面的分析，對其致病機制進行了深入的總結(jié)，并探討了艱難梭菌防治的最新策略和方法，將有利于更好的認識和研究艱難梭菌，為艱難梭菌的防治提供新思路。

關(guān)鍵詞：艱難梭菌；致病機制；防治

來源出版物：現(xiàn)代生物醫(yī)學(xué)進展, 2013, 26(13): 5154-5158

噬菌體療法在耐藥性細菌感染中應(yīng)用的研究進展

李菁華，孫延波

摘要：細菌耐藥性已成為全球性的公共衛(wèi)生問題，特別是“超級細菌”成員的不斷增加使針對細菌感染的抗生素療法面臨前所未有的挑戰(zhàn)。最近，噬菌體療法重新受到人們的關(guān)注，并取得一些重要研究進展。本文作者就早期噬菌體的研究情況、近年來噬菌體療法在動物實驗中的應(yīng)用、臨床試驗的最新實例和噬菌體療法的優(yōu)勢及局限進行綜述。

關(guān)鍵詞：噬菌體；噬菌體療法；細菌耐藥

來源出版物：吉林大學(xué)學(xué)報（醫(yī)學(xué)版）, 2013, 39(3): 630-633

6株超級細菌NDM-1基因環(huán)境研究

程燦燦，芮勇宇

摘要：目的：研究6株超級細菌NDM-1基因環(huán)境，探討耐藥基因水平轉(zhuǎn)移機制。方法：收集耐碳青霉烯的G-桿菌400株，利用PCR方法檢測NDM-1基因，并測序驗證。根據(jù)目前報道的 NDM-1基因環(huán)境常見類型設(shè)計系列引物，步移法特異性擴增 NDM-1基因上下游序列，并對擴增產(chǎn)物測序和序列分析。步移法檢測陰性的菌株進行全基因組HindⅢ酶切，將NDM-1基因及基因環(huán)境克隆到pET28a質(zhì)粒后再測序。結(jié)果：400株對碳青霉烯類耐藥的G-桿菌中有6株NDM-1陽性。步移法檢出其中5株菌的基因環(huán)境，包括不動桿菌基因種13TU、產(chǎn)酸克雷伯菌、不動桿菌基因種 3、肺炎克雷伯菌和陰溝腸桿菌。這5株菌的基因環(huán)境與文獻報道基本一致。產(chǎn)氣腸桿菌的 NDM-1基因環(huán)境經(jīng) DNA克隆測序獲得，從上游至下游為：部分缺失的轉(zhuǎn)座酶Tn3、IS26及ISAbal25，blaNDM-1，ble，部分缺失的異構(gòu)酶trpF和SSen4元件。結(jié)論：NDM-1基因上下游常包含轉(zhuǎn)座子或插入序列等元件，為其水平轉(zhuǎn)移奠定基礎(chǔ)。

關(guān)鍵詞：超級細菌；NDM-1；基因環(huán)境

來源出版物：實用醫(yī)學(xué)雜志, 2013, 20(3): 624-634

攜帶NDM-1陰溝腸桿菌尿路感染株臨床特點回顧性報告

曹麗軍，楊靖，耿鳳珍，等

摘要：目的：對 2012年 7月分離自住院患者尿液標本攜帶 NDM-1陰溝腸桿菌的臨床特點、檢測過程進行回顧性分析，探討其耐藥特征及產(chǎn)生機制，對控制“超級細菌”的流行提出意見。方法：依照 CLSI標準，采用K-B法和MIC法檢測耐藥性，改良Hodge試驗和金屬酶試驗檢測產(chǎn)酶類型，聚合酶鏈反應(yīng)（PCR）檢測耐藥基因并進行測序。結(jié)果：此株陰溝腸桿菌對亞胺培南和美羅培南等 15種 7個類別抗生素均顯示耐藥，改良Hodge試驗陽性，金屬酶表型初篩試驗陽性，經(jīng)基因擴增并測序后，與Genebank比對，表明與NDM-1基因有99%的相似性，并經(jīng)河北省CDC確證報告該菌株為攜帶NDM-1陰溝腸桿菌。結(jié)論：該尿路感染攜帶NDM-1基因金屬酶的陰溝腸桿菌株，其產(chǎn)生可能與患者年老體差、惡性腫瘤伴長時滯留尿管并長時多次應(yīng)用過多種抗生素有關(guān)，因此特別強調(diào)嚴格侵入性導(dǎo)尿及滯留時限指征、規(guī)范抗生素使用，做好重點消毒、隔離，控制多重耐藥株發(fā)生。

關(guān)鍵詞：陰溝腸桿菌；碳青霉烯類抗生素；NDM-1基因檢測；回顧性報告

來源出版物：醫(yī)學(xué)研究與教育, 2014, 31(1): 33-36

新型自組裝納米抗菌肽及抗菌肽藥物研究

馬詩怡，何道航

摘要：一些傳統(tǒng)抗生素隨著超級細菌的出現(xiàn)將面臨著被淘汰的風險，而抗菌肽因其抗菌譜廣、作用機制獨特和不易導(dǎo)致耐藥性等優(yōu)點，有望成為理想的抗生素替代藥物。近年來,隨著肽自組裝納米技術(shù)的迅速發(fā)展，已有多種新型自組裝納米抗菌肽相繼被設(shè)計和制備出來，并具有顯著的體內(nèi)外抗菌活性，展示出其作為新型安全高效抗菌藥物的獨特優(yōu)勢。新型自組裝納米抗菌肽藥物的設(shè)計與研究正成為當前國際前沿熱點，本文就新型自組裝納米抗菌肽及抗菌肽藥物臨床試驗的國內(nèi)外研究進展作了綜述。

關(guān)鍵詞：自組裝；納米抗菌肽；兩親性；抗菌活性；臨床試驗

來源出版物：中國新藥雜志, 2014, 23(2): 203-209

抗生素耐藥性的來源與控制對策

朱永官，歐陽緯瑩，吳楠，等

摘要：抗生素除了大量用于人類疾病的治療外，還作為飼料添加劑被廣泛應(yīng)用于動物養(yǎng)殖業(yè)。微生物的抗生素耐藥性就是指微生物能夠在抗生素存在的情況下生長和繁殖。抗生素耐藥性是環(huán)境微生物固有的，即所謂的內(nèi)在抗性，但是人類大量使用抗生素帶來的抗生素抗性基因的擴散和傳播普遍存在，且已開始威脅到全球人群的健康。微生物對抗生素的抗性主要有3個機制：（1）抗生素的外排；（2）抗生素的降解或修飾；（3）抗生素作用位點的保護。大量研究表明，抗生素的使用和抗生素抗性的蔓延呈現(xiàn)良好的相關(guān)性，而且環(huán)境微生物的抗性可以通過基因橫向轉(zhuǎn)移向人類致病菌擴散，最終可能導(dǎo)致超級細菌的爆發(fā)，直接影響人類健康。為了應(yīng)對全球性的抗生素抗性問題，必須加強（1）全球抗生素使用和環(huán)境排放的監(jiān)管政策和管理體系；（2）建立快速和透明的抗生素耐藥性監(jiān)測體系，使其涵蓋醫(yī)院、養(yǎng)殖業(yè)、污水處理廠等；（3）建立抗生素藥物創(chuàng)新基金，通過政府和企業(yè)的聯(lián)合，加快新型藥物的研制；同時加強知識產(chǎn)權(quán)保護，使新藥創(chuàng)制走上可持續(xù)之路；（4）加強抗生素耐藥性相關(guān)的基礎(chǔ)與應(yīng)用研究，包括耐藥性發(fā)生和傳播的生態(tài)學(xué)機制，消除和緩解耐藥性發(fā)生和傳播的環(huán)境技術(shù)及其系統(tǒng)解決方案等，包括改進污水處理廠的處理工藝，削減出水中抗性基因和抗性菌的比例；（5）加強抗生素耐藥性的科普宣傳,提高全社會對耐藥性的認知能力，從而在源頭上有效控制抗生素在農(nóng)業(yè)和醫(yī)療方面的濫用及其環(huán)境污染。

關(guān)鍵詞：城市化；抗生素；耐藥性；超級細菌；環(huán)境健康

來源出版物：中國科學(xué)院院刊, 2015, 30(4): 509-516

新德里金屬β內(nèi)酰胺酶-1型超級細菌的研究及防控

歐尾妹，呂媛

摘要：新德里金屬β內(nèi)酰胺酶-1（NDM-1）屬于B1亞類金屬β內(nèi)酰胺酶，能水解除氨曲南外的絕大多數(shù)β內(nèi)酰胺類抗菌藥物，其基因大多定位在質(zhì)粒上，易引起水平傳播。人主要是通過院內(nèi)感染、個人旅行和社區(qū)獲得 3種途徑感染產(chǎn) NDM-1細菌。實驗室檢測方法有表型篩查、表型確證和基因確證。本文主要從流行情況、分子生物學(xué)特點、檢測方法、預(yù)防等方面對產(chǎn)NDM-1細菌做一綜述，旨在加強對NDM-1型超級細菌的認識和防控。

關(guān)鍵詞：超級細菌；新德里金屬β內(nèi)酰胺酶—1；金屬β內(nèi)酰胺酶；碳青霉烯類

來源出版物：中國臨床藥理學(xué)雜志, 2015, 31(23): 2362-2365

中國鮑曼不動桿菌感染診治與防控專家共識解讀

周華，周建英，俞云松

摘要：鮑曼不動桿菌是臨床最重要的致病菌之一，其分離率、感染率、耐藥性均呈上升趨勢，成為全球抗感染領(lǐng)域的挑戰(zhàn)，更是目前我國最重要的“超級細菌”，臨床醫(yī)生在鮑曼不動桿菌感染的診斷、治療和預(yù)防控制上存在諸多困惑。為提高鮑曼不動桿菌感染診治與防控水平，遏制我國鮑曼不動桿菌耐藥性和感染流行的快速增長，2012年我國相關(guān)領(lǐng)域的權(quán)威專家完成了《中國鮑曼不動桿菌感染診治與防控專家共識》（以下簡稱共識）。該共識總結(jié)了我國絕大多數(shù)權(quán)威專家對于鮑曼不動桿菌感染診治與防控的寶貴經(jīng)驗，對我國多重耐藥菌的診治與防控做出引領(lǐng)和示范。共識發(fā)表后得到了國內(nèi)專家的認可和好評，本文旨在介紹該共識的主要內(nèi)容，就共識發(fā)表后鮑曼不動桿菌診治方面的新進展做進一步解讀。

關(guān)鍵詞：鮑曼不動桿菌；感染性疾??；臨床實踐指南；共識

來源出版物：中國循證醫(yī)學(xué)雜志, 2016, 16(1): 26-29

中藥抗細菌耐藥性的研究進展

韓飛，幸仁匯，陳琳琦，等

摘要：細菌耐藥性一直是全球關(guān)注的焦點問題，隨著世界范圍內(nèi)化學(xué)藥抗生素的濫用和“超級細菌”的層出不窮，細菌耐藥性對人類的危害愈發(fā)嚴重，且有不可抑制的趨勢。在化學(xué)藥抗生素相對匱乏的今天，人們把更多的目光投向了來源廣泛、安全性高、毒副作用小、抗耐藥機制神秘的中草藥，希望能從中找到解決耐藥性問題的新途徑或新思路。故近年來篩選、提取、分離天然植物及中藥中有效的耐藥抑制劑，探討其抗耐藥性機制，已成為藥學(xué)領(lǐng)域研究的熱點。該文從細菌耐藥性的作用機制，中藥抗細菌耐藥性的特點及優(yōu)勢，抗耐性的中藥成分等幾個方面進行了分析和總結(jié)，希望能為解決細菌耐藥性問題和研發(fā)新型中藥綠色抗生素提供一定的理論基礎(chǔ)及研究思路。

關(guān)鍵詞：細菌；耐藥性；中藥；綠色抗生素

來源出版物：中國中藥雜志, 2016, 41(5): 813-817

淺談超級細菌的耐藥性及診療機制

王逸飛

摘要：2010年8月英國醫(yī)學(xué)期刊《柳葉刀傳染病》雜志報道，在印度、巴基斯坦發(fā)現(xiàn)新型“超級細菌”。隨后，歐洲和亞洲也相繼報道了感染病例，且傳播全球。最近，在細菌群體中出現(xiàn)耐藥基因的傳播，從而再度引起了科學(xué)家們的密切關(guān)注。本文旨在總結(jié)近年來學(xué)者對于超級細菌的認識，耐藥機制，診斷治療及預(yù)防措施。

關(guān)鍵詞：超級細菌；耐藥性；機制

來源出版物：臨床醫(yī)藥文獻電子雜志, 2016, 3(40): 8087-8088

超級細菌疫苗研究進展

鄒全明，石云

摘要：“超級細菌”（superbugs）是指對抗生素有超強耐藥性細菌的統(tǒng)稱。隨著抗生素濫用問題日益嚴重，耐藥細菌不斷出現(xiàn)并呈全球化流行趨勢，“超級細菌”的家族也越來越龐大，已成為引起臨床感染的嚴重病原菌，可能面臨無藥可治的境地。2014年世界衛(wèi)生組織發(fā)布的《抗菌素耐藥：全球監(jiān)測報告》顯示：每年美國因感染超級耐藥細菌而死亡的人數(shù)高達 6.3萬人，歐盟范圍內(nèi)死亡人數(shù)也有 2.5萬人。超級細菌每年在美國造成的死亡人數(shù)遠超過感染艾滋病毒的死亡人數(shù)。若超級細菌在全球范圍的擴散得不到有效遏制，由此造成的死亡人數(shù)每年可能增加 1000萬人。而為應(yīng)對超級細菌蔓延，到2050年，世界需要支出100萬億美元。美國政府于2015年3月27日公布了1項為期5年的國家行動計劃，以應(yīng)對“緊迫而嚴重”的細菌耐抗生素威脅。大力推動這一計劃的美國總統(tǒng)奧巴馬指出：“抗生素耐藥是當今世界面臨的最緊迫的公共衛(wèi)生問題之一”。加速疫苗研發(fā)是對抗細菌耐藥的重要舉措。

關(guān)鍵詞：超級細菌；疫苗；耐甲氧西林金黃色葡萄球菌；銅綠假單胞菌；鮑曼不動桿菌

來源出版物：第三軍醫(yī)大學(xué)學(xué)報, 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

來源出版物：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.

來源出版物：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.

來源出版物：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.

來源出版物：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

來源出版物：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.

來源出版物：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

來源出版物：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

來源出版物：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

來源出版物：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.

來源出版物：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.

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

責任編輯：衛(wèi)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.

來源出版物：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.

來源出版物：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.

來源出版物：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