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，允许两个基因相同的细胞积累实质上不同数量的给定化合物。通过控制这些机制，我将根除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异。表型抗生素耐药性是细菌亚群在抗生素治疗中短暂存活的非遗传能力，引起细菌感染的顽固性。迫切需要开发针对细菌病原体群体中表型耐药变异的抗生素疗法。这对于世卫组织关键优先清单上的ESKAPE病原体尤其重要，因为它们是危及生命的传染病的主要原因，而且往往对抗生素治疗具有抗药性。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，膜运输的细胞间差异驱动细菌表型多样化。DYNBIOTICS采用尖端的生物物理学、组学和数学方法，将i)识别有利于药物积累表型异质性的环境因素；Ii)发现允许表型变异以避免药物积累的生物物理过程和分子机制；Iii)确定新的抗生素-辅助联合疗法，增强抗生素在耐药表型变异中的积累。鉴于目前的抗生素耐药性危机，实现这些目标是非常及时的：为了对抗病原微生物，我们迫切需要使药物在人群中的所有细胞中以生长抑制水平积累。

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.