Bacteria under antibiotic attack: Different strategies for evolutionary adaptation

Abstract

Bacteria are well known for their extremely high adaptability in stressful environments. The clinical relevance of this property is clearly illustrated by the ever-decreasing efficacy of antibiotic therapies. Frequent exposures to antibiotics favor bacterial strains that have acquired mechanisms to overcome drug inhibition and lethality. Many strains, including life-threatening pathogens, exhibit increased antibiotic resistance or tolerance, which considerably complicates clinical practice. Alarmingly, recent studies show that in addition to resistance, tolerance levels of bacterial populations are extremely flexible in an evolutionary context. Here, we summarize laboratory studies providing insight in the evolution of resistance and tolerance and shed light on how the treatment conditions could affect the direction of bacterial evolution under antibiotic stress. Strategies to overcome antibiotic treatment Bacterial populations can adopt different strategies to become refractory to an antibiotic treatment that would otherwise be lethal. The emergence and dissemination of these survival strategies can be the result of either vertical transmission of de novo mutations or horizontal transfer of mobile genetic elements. As horizontal gene transfer (HGT) has proved challenging to track during laboratory evolution, the environmental parameters that affect it remain poorly understood. Despite the importance of HGT, this Review therefore mainly focuses on evolution by de novo mutations, which can easily be monitored in the lab. A well-documented antibiotic survival strategy is resistance, which is usually conferred by genetic changes that allow bacteria to grow at elevated drug concentrations. Resistance is routinely quantified by the minimum inhibitory concentration (MIC), defined as the lowest antibiotic concentration that is required to prevent bacterial growth [1]. However, even populations with a low MIC may display considerable survival when facing antibiotic attack. This is, in many cases, due to antibiotic tolerance, which allows bacteria to survive but not proliferate during a high-dose antibiotic treatment [2]. In contrast to resistant mutants, tolerant cells only differ phenotypically from susceptible cells and can constitute the entire population or be present as a subpopulation of cells. Tolerance in only a fraction of the population is referred to as persistence [3,4]. Throughout the remainder of the text, we will consider persistence as a specific case of tolerance, and we will not make the distinction, since both are similar regarding the phenotype and the evolutionary and clinical consequences.

Evolutionary Pathways and Trajectories in Antibiotic Resistance

“…The evolution of antibiotic tolerance, either by increasing the drug concentration that the bacteria are able to tolerate or increasing the proportion of tolerant variants, is an interesting issue that has been scarcely investigated (406). The number of genes involved in bacterial tolerance (the tolerome) is larger than the number of genes identified for the resistome, suggesting that the evolution of increased tolerance might evolve even faster than antibiotic resistance (390).…”

Sublethal Levels of Antibiotics Promote Bacterial Persistence in Epithelial Cells

“…Compared to the abundant extracellular antibiotics, accumulated antibiotics in cells consisted only about 0.28-14.34% of the total ( Figure S3C, Supporting Information). Given that sufficient levels of antibiotics are prerequisite to inhibit bacterial growth, [13,14,17] such low levels of antibiotics in the cytosol could not reach sufficient concentrations to kill/inhibit bacteria. Thus, we used sublethal levels of antibiotics to treat infected mice and observed that such antibiotics could promote B. cereus internalization ( Figure 3B,C).…”

“…[15] Antibiotic tolerance can facilitate the evolution of antibiotic resistance. [16,17] For instance, Salmonella Typhimurium forms persisters to promote the dissemination of antibiotic resistance plasmids. [18] However, it remains largely unclear what the driving force for the emergence of antibiotic tolerance is, particularly in vivo.…”

Evolution of Antibiotic Tolerance Shapes Resistance Development in Chronic Pseudomonas aeruginosa Infections

“…Recent studies have shown that bacteria can rapidly evolve tolerance and persistence when exposed to antibiotics in vitro (9)(10)(11)(12), suggesting that both represent successful strategies for bacteria to survive antibiotic treatment. In line with this, treatment efficacy during chronic infections was shown to be lost progressively without significant resistance development (13,14).…”