Ismail Alysha S, Berryhill Brandon A, Gil-Gil Teresa, Manuel Joshua A, Smith Andrew P, Baquero Fernando, Levin Bruce R
Department of Biology, Emory University, Atlanta, Georgia, USA.
Program in Microbiology and Molecular Genetics, Graduate Division of Biological and Biomedical Sciences, Laney Graduate School, Emory University, Atlanta, Georgia, USA.
Microbiol Spectr. 2025 Apr;13(4):e0247924. doi: 10.1128/spectrum.02479-24. Epub 2025 Mar 4.
The rational design of the antibiotic treatment of bacterial infections employs these drugs to reach concentrations that exceed the minimum needed to prevent the replication of the target bacteria. However, within a treated patient, spatial and physiological heterogeneity promotes antibiotic gradients such that the concentration of antibiotics at specific sites is below the minimum needed to inhibit bacterial growth. Here, we investigate the effects of sub-inhibitory antibiotic concentrations on three parameters central to bacterial infection and the success of antibiotic treatment, using experiments with and mathematical and computer-simulation models. Our results, using drugs of six different classes, demonstrate that exposure to sub-inhibitory antibiotic concentrations alters bacterial growth dynamics, increases the mutation rate to antibiotic resistance, and decreases the production of persister cells thereby reducing persistence levels. Understanding this trade-off between mutation rates and persistence levels resulting from sub-inhibitory antibiotic exposure is crucial for optimizing, and mitigating the failure of, antibiotic therapy.
Much of the research on antibiotics and antibiotic treatment has focused on drug concentrations sufficient to prevent the growth of bacteria. These concentrations, however, are not always reached everywhere in the body. Here, we look at the effects of exposure to these low concentrations of antibiotics on the common clinically important pathogen . We confirm a previous finding that sub-inhibitory antibiotic exposure decreases the total growth and the growth rate of the bacteria. Moreover, we demonstrate that the level of persistence, an important mechanism for bacteria to survive antibiotics, is decreased due to sub-inhibitory exposure. However, we find that the rate of generation of resistant mutants is substantially increased. Taken together, these results reveal an important trade-off that emerges as a consequence of bacteria being exposed to sub-inhibitory concentrations of antibiotics.
细菌感染抗生素治疗的合理设计是使用这些药物达到超过阻止目标细菌复制所需最低浓度的水平。然而，在接受治疗的患者体内，空间和生理异质性会形成抗生素梯度，使得特定部位的抗生素浓度低于抑制细菌生长所需的最低浓度。在此，我们通过实验以及数学和计算机模拟模型，研究亚抑制性抗生素浓度对细菌感染及抗生素治疗成功与否的三个关键参数的影响。我们使用六种不同类别的药物得出的结果表明，暴露于亚抑制性抗生素浓度会改变细菌生长动态，增加抗生素耐药性的突变率，并减少持留菌细胞的产生，从而降低持续性水平。理解亚抑制性抗生素暴露导致的突变率与持续性水平之间的这种权衡，对于优化抗生素治疗并减轻治疗失败至关重要。
关于抗生素及抗生素治疗的许多研究都集中在足以阻止细菌生长的药物浓度上。然而，这些浓度并非总能在体内各处达到。在此，我们研究暴露于这些低浓度抗生素对常见临床重要病原体的影响。我们证实了之前的一项发现，即亚抑制性抗生素暴露会降低细菌的总生长量和生长速率。此外，我们证明，作为细菌在抗生素作用下存活的一种重要机制，持续性水平会因亚抑制性暴露而降低。然而，我们发现耐药突变体的产生速率大幅增加。综上所述，这些结果揭示了细菌暴露于亚抑制性抗生素浓度时出现的一种重要权衡。
