Development and experimental testing of a new approach to modeling the effect of antimicrobial agents on heterogeneous microbial populations

开发和实验测试一种新方法来模拟抗菌剂对异质微生物种群的影响

基本信息

  • 批准号:
    0730454
  • 负责人:
  • 金额:
    $ 37.79万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
    Standard Grant
  • 财政年份:
    2008
  • 资助国家:
    美国
  • 起止时间:
    2008-01-01 至 2011-12-31
  • 项目状态:
    已结题

项目摘要

PI: Michael Nikolaou and Vincent TamInstitution: University of HoustonProposal Number: 0730454Title: Development and Experimental Testing of a New Approach to Modeling the Effect of Antimicrobial Agents on Heterogeneous Microbial PopulationsMicrobial resistance to antimicrobial agents has reached alarming proportions, creating an all too real threat for society to return to the pre-antibiotics era. This threat makes the rapid development of new antimicrobial agents imperative. Such development takes over a decade, because of the extensive testing of dosing regimens among other tests needed before a candidate agent is approved for use. The criticality of dosing regimen testing is exemplified by the case of daptomycin, an antibiotic whose development (after initial discovery) was abandoned before it was rekindled over a decade later, to reach final FDA approval after the effects of dosing were understood and the right dosing regimen was identified. Despite the importance of dosing regimen testing, guidance to such testing is empirical and may terminate development of promising candidates or lead to dead ends. This research aims to develop and validate in vitro mathematical modeling tools that can guide the testing of dosing regimens. These tools will be based on a mathematical modeling framework that the two co-PIs developed in preliminary research. Experiments will test the effect of three representative antibiotics (meropenem, levofloxacin, tobramycin) on bacterial populations of Pseudomonas aeruginosa of varying resistance. Intellectual Merit The research aims to advance understanding of the dynamic effect of antimicrobial agents on microbial populations comprising subpopulations of varying degrees of resistance to an agent. While the mathematical tools to be developed will be tested experimentally in vitro by investigating the effect of antibacterials on bacterial populations simulating human infections, the same fundamental mathematical framework can be used to investigate the effects of antifungals or antivirals as well as the effect of chemotherapy on cancerous cell populations. This broadens the importance of the research beyond its specific field. The research is likely to come to fruition based on preliminary results by the two co-PIs who have demonstrated the feasibility of the mathematical modeling framework to be employed. That framework uses mathematical concepts (cumulants) that have not been used before for the problem at hand. The two co-PIs form a multi-disciplinary group doing research in both systems theory (dynamics, optimization, and control) and experimental therapeutics (infection models, mechanisms of resistance).Broader Impacts Showcasing the proposed research will help make an appealing case for science and engineering among youth, particularly among racially underrepresented groups (constituting over 60% of the city of Houston), that are routinely recruited by UH and are offered summer internships. The research will help consolidate the collaborative research efforts initiated by the two co-PIs as well as collaboration with the pharmaceutical industry (Astra-Zeneca). The research will have a societal impact by helping combat microbial resistance to antimicrobial agents, a problem that could have dire consequences if it were to remain unsolved.
主要研究者:Michael Nikolaou和Vincent TamInstitution:University of Houston提案编号:0730454标题:开发和实验测试一种新的方法来模拟抗菌剂对异质性微生物种群的影响微生物对抗菌剂的耐药性已经达到了令人担忧的程度,为社会回到前抗生素时代创造了一个真实的威胁。这种威胁使得新的抗菌剂的快速开发势在必行。这种开发需要十多年的时间,因为在候选药物被批准使用之前,需要对给药方案进行广泛的测试。达托霉素是一种抗生素,其开发(在最初发现后)在十多年后重新启动之前被放弃,以便在了解给药效果并确定正确的给药方案后获得最终FDA批准。尽管给药方案测试很重要,但对此类测试的指导是经验性的,可能会终止有希望的候选药物的开发或导致死胡同。本研究旨在开发和验证体外数学建模工具,以指导给药方案的测试。这些工具将基于两个co-PI在初步研究中开发的数学建模框架。实验将测试三种代表性抗生素(美罗培南、左氧氟沙星、妥布霉素)对不同耐药性铜绿假单胞菌细菌种群的影响。 该研究旨在促进对抗菌剂对微生物种群的动态影响的理解,微生物种群包括对药剂具有不同程度抗性的亚群。虽然要开发的数学工具将通过研究抗菌药物对模拟人类感染的细菌种群的影响进行体外实验测试,但相同的基本数学框架可用于研究抗真菌药或抗病毒药的影响以及化疗对癌细胞群的影响。这扩大了研究的重要性超出其特定领域。根据两位共同研究员的初步研究结果,这项研究很可能会取得成果,他们已经证明了所采用的数学模型框架的可行性。该框架使用了以前从未用于当前问题的数学概念(累积量)。这两个联合PI形成了一个多学科小组,在两个系统理论方面进行研究(动力学,优化和控制)和实验治疗学更广泛的影响展示拟议中的研究将有助于在年轻人中,特别是在种族代表性不足的群体中,为科学和工程学提出有吸引力的理由(占休斯顿市的60%以上),这是由UH定期招聘,并提供暑期实习。这项研究将有助于巩固由两个合作PI发起的合作研究工作以及与制药行业(阿斯利康)的合作。这项研究将通过帮助对抗微生物对抗菌剂的耐药性而产生社会影响,如果这个问题得不到解决,可能会产生可怕的后果。

项目成果

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Michael Nikolaou其他文献

emIn vitro/em model to simulate multiple drugs with distinct elimination half-lives
体外模型模拟具有不同消除半衰期的多种药物
  • DOI:
    10.1016/j.ijantimicag.2023.106924
  • 发表时间:
    2023-10-01
  • 期刊:
  • 影响因子:
    4.600
  • 作者:
    Cole S. Hudson;James E. Smith;Brianna M. Eales;Michael Nikolaou;Vincent H. Tam
  • 通讯作者:
    Vincent H. Tam
Optimizing the logistics of compressed natural gas transportation by marine vessels
  • DOI:
    10.1016/j.jngse.2010.02.001
  • 发表时间:
    2010-03-01
  • 期刊:
  • 影响因子:
  • 作者:
    Michael Nikolaou
  • 通讯作者:
    Michael Nikolaou
Advantage of miscible fluid injection and tight oil production through a single-well alternating production-injection procedure over other single-well EOR methods
  • DOI:
    10.1016/j.petrol.2020.108091
  • 发表时间:
    2021-04-01
  • 期刊:
  • 影响因子:
  • 作者:
    Guofan Luo;Christine Ehlig-Economides;Michael Nikolaou
  • 通讯作者:
    Michael Nikolaou
Control of snack food manufacturing systems
休闲食品制造系统的控制
  • DOI:
  • 发表时间:
    2006
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Michael Nikolaou
  • 通讯作者:
    Michael Nikolaou
Systematic design of pulse dosing to eradicate persister bacteria: The case of fluoroquinolones
脉冲给药的系统设计以根除持久性细菌:以氟喹诺酮类药物为例
  • DOI:
    10.1016/j.compchemeng.2025.109010
  • 发表时间:
    2025-04-01
  • 期刊:
  • 影响因子:
    3.900
  • 作者:
    Garima Singh;Sayed Golam Mohiuddin;Sreyashi Ghosh;Jenet Narzary;Mehmet A. Orman;Michael Nikolaou
  • 通讯作者:
    Michael Nikolaou

Michael Nikolaou的其他文献

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{{ truncateString('Michael Nikolaou', 18)}}的其他基金

Adaptive Design of Experiments for Optimal Uniformity in Semiconductor Manufacturing
半导体制造中最佳均匀性实验的自适应设计
  • 批准号:
    0227232
  • 财政年份:
    2003
  • 资助金额:
    $ 37.79万
  • 项目类别:
    Continuing Grant
SGER: A Study on Plasma Etching Yield Improvements through a Faculty-in-Industry Internship
SGER:通过行业内实习提高等离子蚀刻产量的研究
  • 批准号:
    0118516
  • 财政年份:
    2001
  • 资助金额:
    $ 37.79万
  • 项目类别:
    Standard Grant
Design of Constrained Model-Predictive Control Systems with Increased Autonomy
具有增强自主性的约束模型预测控制系统的设计
  • 批准号:
    9896231
  • 财政年份:
    1998
  • 资助金额:
    $ 37.79万
  • 项目类别:
    Standard Grant
Design of Constrained Model-Predictive Control Systems with Increased Autonomy
具有增强自主性的约束模型预测控制系统的设计
  • 批准号:
    9615979
  • 财政年份:
    1997
  • 资助金额:
    $ 37.79万
  • 项目类别:
    Standard Grant
Research Initiation Award: A Comprehensive Controller Design Methodology for Nonlinear Processes
研究启动奖:非线性过程综合控制器设计方法
  • 批准号:
    9009376
  • 财政年份:
    1990
  • 资助金额:
    $ 37.79万
  • 项目类别:
    Standard Grant

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