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

PI：Michael Nikolaou和文森特·塔姆研究所：休斯顿大学提议编号：0730454题目：抗菌剂对异质微生物种群影响建模的新方法的开发和实验测试抗菌剂的抗药性已经达到令人震惊的程度，给社会回到抗生素之前的时代造成了太大的现实威胁。这种威胁使得快速开发新的抗菌剂势在必行。这样的开发需要十多年的时间，因为在候选试剂被批准使用之前，除了其他测试外，还需要对剂量方案进行广泛的测试。剂量方案测试的关键是达托霉素的案例，这是一种抗生素，其开发(在最初发现后)被放弃，直到十多年后重新点燃，在了解剂量的影响并确定正确的剂量方案后，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可指导给药方案测试的体外数学建模工具。这些工具将基于两个共同的绩效指标在初步研究中开发的数学建模框架。实验将测试三种有代表性的抗生素(美罗培南、左氧氟沙星、妥布霉素)对不同耐药性的铜绿假单胞菌种群的影响。智力价值这项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某种制剂具有不同程度抗药性的亚群。虽然将开发的数学工具将通过调查抗菌剂对模拟人类感染的细菌种群的影响进行体外实验测试，但同样的基本数学框架也可以用于研究抗真菌或抗病毒药物的影响以及化疗对癌细胞种群的影响。这扩大了研究的重要性，超出了其特定的领域。这项研究很可能基于两个共同的个人投资项目的初步结果，他们已经证明了所采用的数学建模框架的可行性。该框架使用了以前从未用于手头问题的数学概念(累积量)。这两个共同的PIs组成了一个多学科小组，从事系统理论(动力学、优化和控制)和实验治疗学(感染模型、耐药机制)的研究。展示拟议研究的广泛影响将有助于在年轻人中提供科学和工程方面的吸引力案例，特别是在种族代表性不足的群体(占休斯顿市60%以上)中，这些群体经常被休斯敦大学招聘，并获得暑期实习机会。这项研究将有助于巩固由两个共同投资促进机构发起的合作研究努力，以及与制药行业(阿斯特拉-捷利康)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，如果不解决这个问题，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.