Towards drugs that prevent resistance to the HIV OI, TB

寻找预防 HIV OI、TB 耐药性的药物

基本信息

批准号：
7028846
负责人：
David Alland
金额：
$ 18.6万
依托单位：
UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-03-01 至 2009-02-28
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): This proposal is to perform preliminary studies that will ultimately result in antibiotics with synergistic activity against the HTV opportunistic pathogen, Mycobacterium tuberculosis (TB). TB is the leading cause of death among HTV-infected patients in the developing world. This bacterium predictably becomes resistant to each drug soon after it is introduced. A new approach is required that specifically prevents the emergence of drug resistance and its transmission between patients. We have discovered that mutations in codon 306 of the TB embB gene predisposes strains to acquire progressively more drug resistance and increases their potential for transmission, although the mutation does not cause resistance to any given drug on its own. Here, we propose to determine the mechanisms underlying these observations, with the ultimate goal of designing drugs that inhibit this activity. We hypothesize that the drug ethambutol (EMB) normally acts synergistically with other antibiotics to prevent the emergence of drug resistance, and that this synergy is lost in embB306 mutants. This synergy appears to be effective below the minimal inhibitory concentration of EMB. To better understand this process, we will investigate whether EMB-associated inhibition of lipoarabinomannam (LAM) biosynthesis increases the permeability of the TB cell wall to antibiotics and results in synergy. We will also investigate whether increased intracellular antibiotics can delay the development of drug resistance. Finally we will study whether EMB-inhibition of LAM modulates the early interactions between TB and the immune system, potentially explaining the increased transmissibility seen in the embB306 mutants. Experiments with wild type and embB3Q6 mutant strains will be performed in parallel to determine if embB306 mutants are resistant to these novel effects of EMB. Our specific aims are to determine in vitro: 1. if EMB causes synergistic with other antibiotics by increasing antibiotic permeability, and if embB306 mutants are resistant to this synergy; 2. if embB306 mutants have altered phagocytosis, growth and cytokine induction in macrophages and dendritic cells with and without EMB treatment; 3. if embB306 mutants are more likely than wild type strains to become resistant to other drugs in vitro; 4. if embB306 mutations affect biosynthesis of LAM, capped LAM, arabinogalactan (AG) or other cell wall components in the presence and absence of EMB.

描述（由申请人提供）：本提案旨在进行初步研究，最终产生针对 HTV 机会致病菌结核分枝杆菌 (TB) 具有协同活性的抗生素。结核病是发展中国家艾滋病病毒感染者死亡的主要原因。可以预见的是，这种细菌在每种药物引入后不久就会对其产生耐药性。需要一种新方法来专门防止耐药性的出现及其在患者之间的传播。我们发现，结核病 embB 基因密码子 306 的突变使菌株容易获得逐渐增强的耐药性，并增加其传播的潜力，尽管该突变本身不会导致对任何给定药物的耐药性。在这里，我们建议确定这些观察结果背后的机制，最终目标是设计抑制这种活性的药物。我们假设药物乙胺丁醇 (EMB) 通常与其他抗生素协同作用，以防止耐药性的出现，而这种协同作用在 embB306 突变体中消失。这种协同作用似乎在低于 EMB 的最低抑制浓度时有效。为了更好地理解这一过程，我们将研究 EMB 相关的阿拉伯脂甘露聚糖 (LAM) 生物合成抑制是否会增加结核细胞壁对抗生素的通透性并产生协同作用。我们还将研究增加细胞内抗生素是否可以延缓耐药性的发展。最后，我们将研究 LAM 的 EMB 抑制是否调节 TB 与免疫系统之间的早期相互作用，这可能解释 embB306 突变体中传播性增加的原因。将同时进行野生型和 embB3Q6 突变株的实验，以确定 embB306 突变株是否对 EMB 的这些新作用具有抵抗力。我们的具体目标是在体外确定： 1. EMB 是否通过增加抗生素渗透性与其他抗生素产生协同作用，以及 embB306 突变体是否对这种协同作用具有抗性； 2.无论是否经过EMB处理，embB306突变体是否改变了巨噬细胞和树突状细胞的吞噬作用、生长和细胞因子诱导； 3. embB306突变体是否比野生型菌株更有可能在体外对其他药物产生耐药性； 4.在存在或不存在EMB的情况下，embB306突变是否影响LAM、加帽LAM、阿拉伯半乳聚糖(AG)或其他细胞壁成分的生物合成。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Allelic exchange and mutant selection demonstrate that common clinical embCAB gene mutations only modestly increase resistance to ethambutol in Mycobacterium tuberculosis.

等位基因交换和突变体选择表明，常见的临床 embCAB 基因突变仅适度增加结核分枝杆菌对乙胺丁醇的耐药性。

DOI：
发表时间：
2010-01
期刊：
影响因子：
4.9
作者：
Safi, Hassan;Fleischmann, Robert D;Peterson, Scott N;Jones, Marcus B;Jarrahi, Behnam;Alland, David
通讯作者：
Alland, David