Numerical experimental data for all figures.
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Growth rate plays a fundamental role in microbiology and serves as an important proxy for fitness in evolution. While high-throughput measurements of bacterial growth rates are easily performed in any microbiology laboratory, similar methods are lacking for bacteriophages. This gap hinders systematic comparisons of important phage phenotypes, such as their amplification rate in bacterial populations and their bactericidal effect, across different phages and environmental conditions. Here, we show that the amplification rate of lytic phages can be quantified by analyzing bacterial population growth and collapse dynamics under phage predation using a parsimonious mathematical model – an approach termed Phage-Host Observation for Rate estimation from Collapse Events (PHORCE). We found that the resulting phage amplification rate captures the bactericidal effect independent of initial phage and bacterial population sizes for fast-growing hosts and adsorption-limited phages. Using high-throughput PHORCE, we found that the amplification rates of Escherichia coli phages vary widely by more than three orders of magnitude. Furthermore, our approach suggests that phage–antibiotic interactions are predominantly determined by the antibiotic, and not by the phage. In particular, the ribosome-inhibiting antibiotic doxycycline generally showed antagonism with phage amplification, whereas the DNA-damaging antibiotic nitrofurantoin was synergistic. This framework provides a means to quantitatively characterize phage phenotypes and may facilitate future high-throughput phage screens for antibacterial applications.
生长速率在微生物学中具有核心地位,同时也是进化过程中适合度的重要替代指标。尽管在任意微生物实验室中均可轻松完成细菌生长速率的高通量(high-throughput)测定,但目前尚缺乏针对噬菌体(bacteriophages)的类似方法。这一研究缺口阻碍了不同噬菌体与环境条件下重要噬菌体表型的系统性比较,例如其在细菌种群中的扩增速率与杀菌效果。本研究表明,通过采用简约数学模型分析噬菌体侵染下的细菌种群生长与裂解动态,可以定量测定裂解性噬菌体(lytic phages)的扩增速率——该方法被命名为基于裂解事件的噬菌体-宿主观测速率估算法(Phage-Host Observation for Rate estimation from Collapse Events,缩写PHORCE)。研究发现,对于快速生长的宿主菌与吸附受限的噬菌体,所得到的噬菌体扩增速率能够反映其杀菌效果,且该效果不受初始噬菌体与细菌种群数量的影响。通过高通量PHORCE方法,我们发现大肠杆菌(Escherichia coli)噬菌体的扩增速率差异可达三个数量级以上。此外,本研究方法表明,噬菌体-抗生素相互作用主要由抗生素而非噬菌体决定。具体而言,抑制核糖体的抗生素多西环素(doxycycline)通常与噬菌体扩增表现出拮抗作用,而损伤DNA的抗生素呋喃妥因(nitrofurantoin)则与噬菌体扩增表现出协同作用。该框架为定量表征噬菌体表型提供了可行手段,有望推动未来用于抗菌应用的高通量噬菌体筛选工作。



