The differing biological fates of DNA minor groove-binding (MGB) antibiotics in Gram-negative and Gram-Positive bacteria.

DNA 小沟结合 (MGB) 抗生素在革兰氏阴性和革兰氏阳性细菌中的不同生物学命运。

• 批准号: BB/K019600/1
• 负责人: Nicholas Tucker
• 金额: $ 47.12万
• 依托单位: University of Strathclyde
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FK019600%2F1
• 关键词: differing; biological; fates; DNA; minor

Antibiotics have been at the forefront of our fight against infectious disease since the 1940's. Since that time our reliance on antibiotics has been exposed by the rise of antibiotic resistant bacteria such as methicillin resistant Staphylococcus aureus (MRSA). Unfortunately, MRSA is not alone in its ability to resist the effects of antibiotics; other organisms such as Pseudomonas aeruginosa also have this ability. The World Health Organization considers solving the antibiotic resistance problem to be of global importance. One way of solving this problem is through the academic innovation of new antibiotic drugs to fight infectious disease.We have been studying a group of compounds called MGBs that have very high activity against MRSA. Very little is known about the biological basis for this activity and we will determine the mode of action of these new drugs. We hypothesise that MGBs interfere with the ability of MRSA to control the use of its genes during infection. We will identify which genes are most potently inhibited by our new antibiotics providing us with a detailed set of targets. This information will be used in two ways. Firstly, knowledge of the targets of our drugs will help us to design new compounds that favour particular genes. Secondly, knowledge of the mode of action of a drug is important for gaining approval to use the drug in clinical trials and ultimately, the clinic.Our previous research suggests that MGBs exhibit much better activity against organisms such as MRSA compared to Pseudomonas and E. coli. We hypothesise that this is because the latter two organisms are capable of expelling the MGBs from their cells using a system of pumps in the membrane. We will use cutting edge DNA sequencing technology to identify the resistance mechanisms of these bacteria and use this information to design new and better antibiotic MGBs to treat these infections in the future.

自20世纪40年代以来，抗生素一直处于我们对抗传染病的最前沿。从那时起，耐甲氧西林金黄色葡萄球菌（MRSA）等抗生素耐药细菌的兴起暴露了我们对抗生素的依赖。不幸的是，耐甲氧西林金黄色葡萄球菌并不是唯一具有抵抗抗生素作用的能力;其他生物体如铜绿假单胞菌也具有这种能力。世界卫生组织认为解决抗生素耐药性问题具有全球重要性。解决这个问题的一种方法是通过学术创新的新抗生素药物来对抗传染病。我们一直在研究一组称为MGBs的化合物，它们对MRSA具有非常高的活性。关于这种活性的生物学基础知之甚少，我们将确定这些新药的作用方式。我们假设MGB干扰MRSA在感染过程中控制其基因使用的能力。我们将确定哪些基因被我们的新抗生素最有效地抑制，为我们提供一套详细的靶点。这些信息将以两种方式使用。首先，对药物靶点的了解将帮助我们设计出有利于特定基因的新化合物。其次，了解药物的作用方式对于获得批准在临床试验中使用药物并最终用于临床非常重要。我们以前的研究表明，与假单胞菌和大肠杆菌相比，MGBs对MRSA等微生物表现出更好的活性。杆菌我们假设这是因为后两种生物体能够使用膜中的泵系统将MGBs从其细胞中排出。我们将使用尖端的DNA测序技术来确定这些细菌的耐药机制，并利用这些信息来设计新的和更好的抗生素MGB，以治疗这些感染。

项目成果

Community-led comparative genomic and phenotypic analysis of the aquaculture pathogen Pseudomonas baetica a390T sequenced by Ion semiconductor and Nanopore technologies.

• DOI: 10.1093/femsle/fny069
• 发表时间: 2018-05-01
• 期刊: FEMS microbiology letters
• 影响因子: 2.1
• 作者: Beaton A;Lood C;Cunningham-Oakes E;MacFadyen A;Mullins AJ;Bestawy WE;Botelho J;Chevalier S;Coleman S;Dalzell C;Dolan SK;Faccenda A;Ghequire MGK;Higgins S;Kutschera A;Murray J;Redway M;Salih T;da Silva AC;Smith BA;Smits N;Thomson R;Woodcock S;Welch M;Cornelis P;Lavigne R;van Noort V;Tucker NP
• 通讯作者: Tucker NP

Clinical utilization of genomics data produced by the international Pseudomonas aeruginosa consortium.

• DOI: 10.3389/fmicb.2015.01036
• 发表时间: 2015
• 期刊: Frontiers in microbiology
• 影响因子: 5.2
• 作者: Freschi L;Jeukens J;Kukavica-Ibrulj I;Boyle B;Dupont MJ;Laroche J;Larose S;Maaroufi H;Fothergill JL;Moore M;Winsor GL;Aaron SD;Barbeau J;Bell SC;Burns JL;Camara M;Cantin A;Charette SJ;Dewar K;Déziel É;Grimwood K;Hancock RE;Harrison JJ;Heeb S;Jelsbak L;Jia B;Kenna DT;Kidd TJ;Klockgether J;Lam JS;Lamont IL;Lewenza S;Loman N;Malouin F;Manos J;McArthur AG;McKeown J;Milot J;Naghra H;Nguyen D;Pereira SK;Perron GG;Pirnay JP;Rainey PB;Rousseau S;Santos PM;Stephenson A;Taylor V;Turton JF;Waglechner N;Williams P;Thrane SW;Wright GD;Brinkman FS;Tucker NP;Tümmler B;Winstanley C;Levesque RC
• 通讯作者: Levesque RC

Phenotypic and Genotypic Characteristics of Small Colony Variants and Their Role in Chronic Infection.

• DOI: 10.4137/mbi.s25800
• 发表时间: 2015
• 期刊: Microbiology insights
• 作者: Johns BE;Purdy KJ;Tucker NP;Maddocks SE
• 通讯作者: Maddocks SE

Genomics of antibiotic-resistance prediction in Pseudomonas aeruginosa.

• DOI: 10.1111/nyas.13358
• 发表时间: 2019-01
• 期刊: Annals of the New York Academy of Sciences
• 影响因子: 5.2
• 作者: Jeukens J;Freschi L;Kukavica-Ibrulj I;Emond-Rheault JG;Tucker NP;Levesque RC
• 通讯作者: Levesque RC

Emergence of an Australian-like pstS -null vancomycin resistant Enterococcus faecium clone in Scotland

苏格兰出现类似澳大利亚 pstS 的万古霉素抗性屎肠球菌克隆

• DOI: 10.1101/236786
• 发表时间: 2017
• 作者: Lemonidis K