Growth productivity as a determinant of the inoculum effect for bactericidal antibiotics

Understanding the mechanisms by which populations of bacteria resist antibiotics has implications for evolution, microbial ecology, and public health. The inoculum effect (IE), where antibiotic efficacy declines as the density of a bacterial population increases, has been observed for multiple bacterial species and antibiotics. Several mechanisms to account for IE have been proposed, but most lack experimental evidence or cannot explain IE for multiple antibiotics. We show that growth productivity, the combined effect of growth and metabolism, can account for IE for multiple bactericidal antibiotics and bacterial species. Guided by flux balance analysis and whole genome modeling, we show that the carbon source supplied in the growth medium determines growth productivity. If growth productivity is sufficiently high, IE is eliminated. Our results may lead to approaches to reduce IE in the clinic, help standardize the analysis of new antibiotics, and further our understanding of how bacter..., ,

解析细菌种群对抗生素的抗性机制，对进化生物学、微生物生态学以及公共卫生领域均具有重要意义。接种物效应（Inoculum Effect, IE）指抗生素的抗菌效力随细菌种群密度升高而下降，该现象已在多种细菌与抗生素体系中被观测到。目前已提出多种解释接种物效应的机制，但绝大多数要么缺乏实验证据支撑，要么无法覆盖多种抗生素下的接种物效应。本研究证实，生长生产力（即生长与代谢的综合效应）能够解释多种杀菌类抗生素与细菌物种对应的接种物效应。本研究基于通量平衡分析（Flux Balance Analysis）与全基因组建模（Whole Genome Modeling）开展推导，证实生长培养基中添加的碳源决定了生长生产力水平。当生长生产力达到足够高的水平时，接种物效应将被消除。本研究结果有望为临床中降低接种物效应提供可行方案，助力新型抗生素的分析标准化，并进一步加深我们对杀菌类...