Abstract
The molecular underpinnings of antibiotic resistance are increasingly understood, but less is known about how these molecular events influence microbial dynamics on the population scale. Here, we show that the dynamics of E. faecalis communities exposed to antibiotics can be surprisingly rich, revealing scenarios where increasing population size or delaying drug exposure can promote population collapse. Specifically, we demonstrate how density-dependent feedback loops couple population growth and antibiotic efficacy when communities include drug-resistant subpopulations, leading to a wide range of behavior, including population survival, collapse, or one of two qualitatively distinct bistable behaviors where survival is favored in either small or large populations. These dynamics reflect competing density-dependent effects of different subpopulations, with growth of drug-sensitive cells increasing but growth of drug-resistant cells decreasing effective drug inhibition. Finally, we demonstrate how populations receiving immediate drug influx may sometimes thrive, while identical populations exposed to delayed drug influx collapse.
Highlights
Antibiotic resistance is a growing public health threat [1]
Resistant and sensitive populations exhibit opposing density-dependent effects on antibiotic inhibition To investigate the dynamics of E. faecalis populations exposed to β-lactams, we first engineered drug resistant E. faecalis strains that contain a multicopy plasmid that constitutively expresses β-lactamase (Methods)
We found that the IC50 for sensitive strains is relatively insensitive to inoculum density over this range, while β-lactam producing resistant cells exhibit strong inoculum effects (IE) and show no inhibition for inoculum densities greater than 10−5 (OD units) even at the highest drug concentrations (10 μg/mL)
Summary
Antibiotic resistance is a growing public health threat [1]. Decades of rapid progress fueled by advances in microbiology, genomics, and structural biology have led to a detailed but still growing understanding of the molecular mechanisms underlying resistance [2]. Recent studies have shown that drug resistance can be a collective phenomenon driven by emergent community-level dynamics [3, 4]. Drug degradation by a sub-population of enzyme-producing cells can lead to cooperative resistance that allows sensitive (non-producing) cells to survive at otherwise inhibitory drug concentrations [5, 6, 7].
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