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

University Of Houston, Houston TX

Investigators

Abstract

PI: Michael Nikolaou and Vincent Tam Institution: University of Houston Proposal Number: 0730454 Title: Development and Experimental Testing of a New Approach to Modeling the Effect of Antimicrobial Agents on Heterogeneous Microbial Populations Microbial 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.