DYNBIOTICS - Understanding the dynamics of antibiotics transport in individual bacteria

DYNBIOTICS将确定生物物理过程和分子机制，这些过程和分子机制允许两个遗传相同的细胞积累大量不同数量的给定化合物。通过控制这些机制，我将根除抵抗抗生素、导致药物治疗失败和危及生命的传染病的表型细菌变种。表型抗生素耐药性是指细菌亚群在抗生素治疗后暂时存活的非遗传性能力，导致细菌感染的顽固性。迫切需要开发针对细菌病原体群体中的表型耐药变异的抗生素疗法。对于属于世卫组织关键优先事项清单的ESKAPE病原体来说，这一点尤其重要，因为它们是威胁生命的传染病的主要原因，而且往往抵制抗生素治疗。然而，由于缺乏在单个细菌水平上表征抗生素积累动态的方法，人们对抗生素积累的细胞间差异对表型抗生素耐药性的影响知之甚少。在这里，我假设，在没有遗传变异的情况下，膜转运中的细胞间差异推动细菌表型多样化。利用尖端的生物物理、组学和数学方法，DYNBIOTICS将：i)确定有利于药物积累表型异质性的环境因素；ii)发现允许表型变异避免药物积累的生物物理过程和分子机制；iii)确定新型抗生素-辅助剂组合疗法，以加强抗药性表型变异中的抗生素积累。考虑到目前的抗生素耐药性危机，实现这些目标是非常及时的：为了对抗病原体，我们迫切需要使药物在种群内所有细胞中的生长抑制水平上积累。

DYNBIOTICS will determine the biophysical processes and molecular mechanisms that permit two genetically identical cells to accumulate substantially different quantities of a given compound. By controlling such mechanisms I will eradicate phenotypic bacterial variants that resist antibiotics causing drug treatment failure and life-threatening infectious diseases. Phenotypic antibiotic resistance is the non-heritable capability of bacterial subpopulations to transiently survive antibiotic treatment causing the recalcitrance of bacterial infections. There is an urgent need to develop antibiotic therapies against phenotypic resistant variants within populations of bacterial pathogens. This is particularly important in the case of ESKAPE pathogens that are in the WHO critical priority list since they represent a major cause of life-threatening infectious diseases and often resist antibiotic treatment. However, little is known about the impact of cell-to-cell differences in antibiotic accumulation on phenotypic antibiotic resistance because of a paucity of methods to characterise the dynamics of antibiotic accumulation at the level of the individual bacterium. Here I hypothesise that cell-to-cell differences in membrane transport drive bacterial phenotypic diversification in the absence of genetic variations. Using cutting-edge biophysical, omics and mathematical approaches, DYNBIOTICS will i) identify environmental factors that favour phenotypic heterogeneity in drug accumulation; ii) discover the biophysical processes and molecular mechanisms that permit phenotypic variants to avoid drug accumulation; iii) identify novel antibiotic-adjuvant combination therapies that enhance antibiotic accumulation in drug-resistant phenotypic variants. Achieving these aims is very timely given the current antibiotic resistance crisis: in order to fight pathogenic microbes we urgently need to make drugs accumulate at growth inhibitory levels in all cells within a population.