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

项目负责人：Michael Nikolaou和Vincent TamInstitution: University of houston提案号：0730454标题：一种模拟抗菌剂对异种微生物种群影响的新方法的开发和实验测试微生物对抗菌剂的耐药性已经达到了惊人的比例，为社会回到前抗生素时代创造了一个实在的威胁。这一威胁使得迅速开发新的抗微生物药物势在必行。这种开发需要十多年的时间，因为在批准使用候选药物之前，需要进行大量的给药方案测试和其他测试。达托霉素是一种抗生素，它的开发（在最初的发现之后）被放弃，直到十多年后才重新开始，在了解了剂量的影响并确定了正确的给药方案后，才获得FDA的最终批准。尽管给药方案测试很重要，但对这种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合作项目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菌群的影响。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，这些微生物种群包括对一种抗菌剂具有不同程度耐药性的亚种群。虽然要开发的数学工具将通过研究抗菌药对模拟人类感染的细菌种群的影响在体外实验中进行测试，但同样的基本数学框架可用于研究抗真菌药或抗病毒药物的作用以及化疗对癌细胞种群的影响。这扩大了研究的重要性，超出了它的特定领域。根据两位合作项目负责人的初步结果，这项研究可能会取得成果，他们已经证明了将要采用的数学建模框架的可行性。该框架使用以前未用于当前问题的数学概念（累积量）。这两个合作项目组成了一个多学科小组，在系统理论（动力学、优化和控制）和实验治疗（感染模型、耐药机制）方面进行研究。更广泛的影响展示拟议的研究将有助于在青年中，特别是在种族代表性不足的群体（占休斯顿市的60%以上）中，为科学和工程提供一个有吸引力的案例，这些群体通常被休斯敦大学招募并提供暑期实习机会。这项研究将有助于巩固由两家合作研究机构发起的合作研究努力，以及与制药行业（阿斯特拉-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。

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.