Population Density Modulates Antibiotic Efficacy, Treatment Bistability, and the Evolution of Resistance in Bacteria

By Kevin Wood

Biophysics, University of Michigan, Ann Arbor, MI

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The inoculum effect (IE) is an increase in the minimum inhibitory concentration (MIC) of an antibiotic as a function of the initial size of a microbial population. However, classical measurements of the IE involve growing populations, and population density changes by many orders of magnitude on the timescale of the experiment. Therefore, the functional relationship between population density and antibiotic inhibition is generally not known, leaving many questions about the impact of the IE on different treatment strategies unanswered. In this talk, I will discuss our recent work to address these questions by measuring real-time per capita growth of Enterococcus faecalis populations at fixed population densities using multiplexed computer-automated culture devices. We show that density-dependent growth inhibition is pervasive for commonly used antibiotics, with some drugs showing increased inhibition and others decreased inhibition at high densities. For several drugs, the density dependence is mediated by changes in extracellular pH, a community-level phenomenon not previously linked with the IE. Using a simple mathematical model, we demonstrate how this density dependence can modulate population dynamics in constant drug environments and lead to bistable treatment outcomes in a pharmacological model of antibiotic treatment.  Finally, I will discuss our ongoing work to understand the effects of density fluctuations on the evolution of drug resistance.


Dr. Wood obtained his Ph.D in Theoretical Physics (Condensed Matter / Statistical Physics) at  UCSD with Katja Lindenberg and did postdocs in single molecule Biophysics at Harvard with Sunney Xie, and Systems Biology at Harvard with Philippe Cluzel.

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Researchers should cite this work as follows:

  • Kevin Wood (2016), "Population Density Modulates Antibiotic Efficacy, Treatment Bistability, and the Evolution of Resistance in Bacteria," http://nanohub.org/resources/25410.

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