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.
Keywords: E. faecalis; enterococci; enterococcus; infectious disease; microbiology; physics of living systems.
Antibiotic resistance is a threat to human and animal health worldwide. Although we rely on antibiotics to treat diseases caused by bacteria, such as tuberculosis, some bacteria are already resistant to many of the drugs available. Understanding the basis of resistance is crucial for developing new antibiotics, and for using current drugs more efficiently. One way that bacteria resist antibiotics is by producing enzymes that inactivate specific drugs. If a community of bacteria contains both vulnerable and resistant cells, this can lead to a phenomenon called ‘cooperative resistance’. When treated with antibiotics, vulnerable cells within the group are shielded by their resistant neighbors, which effectively remove the drugs from the environment. Cooperative resistance can make it difficult for researchers to understand how resistance develops in different bacterial populations. This is because a large group of cells may collectively behave in a different way than individual cells. This means that bacterial populations are a more realistic model for ‘real-world’ infections and disease than studies of single cells. Now, Hallinen, Karslake and Wood show how cooperation between cells affects the way bacterial communities respond to beta-lactams, the most commonly prescribed class of antibiotic drugs. Experiments using cultures of Enterococcus faecalis, a bacterium that often causes hospital infections, revealed that the density of different bacterial populations changes the effectiveness of drugs. Although increased cell density had a protective effect on populations containing only resistant bacteria, it made non-resistant populations even more vulnerable. Mathematical modelling using information from the culture experiments predicted that interactions between vulnerable and resistant bacteria within a mixed community can determine how populations change over time. For example, if the number of antibiotic-sensitive cells is too high, this can cause the entire population to collapse. These predictions contradict the conventional understanding of how antibiotic resistance spreads, where small numbers of resistant cells multiply rapidly at the expense of vulnerable ones. These results shed new light on the complex dynamics of antibiotic resistance within bacterial populations as a whole. In the future, they may inspire new ecology-based strategies for slowing the spread of resistance, ultimately helping reduce the burden of disease.
© 2020, Hallinen et al.