DYNBIOTICS - Understanding the dynamics of antibiotics transport in individual bacteria

DYNBIOTICS - 了解抗生素在单个细菌中转运的动态

• 批准号: EP/Y023528/1
• 负责人: Stefano Pagliara
• 金额: $ 215.83万
• 依托单位: UNIVERSITY OF EXETER
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FY023528%2F1
• 关键词: DYNBIOTICS; Understanding; dynamics; antibiotics; transport

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.

DYNBIOTICS 将确定生物物理过程和分子机制，使两个基因相同的细胞能够积累数量显着不同的给定化合物。通过控制这些机制，我将根除对抗生素产生耐药性、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下短暂存活的非遗传能力，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表型耐药变异的抗生素疗法。这对于 WHO 优先考虑名单中的 ESKAPE 病原体尤为重要，因为它们是危及生命的传染病的主要原因，并且常常对抗生素治疗产生抵抗力。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，我假设细胞间膜运输的差异在没有遗传变异的情况下驱动细菌表型多样化。使用尖端的生物物理、组学和数学方法，DYNBIOTICS 将 i) 识别有利于药物积累表型异质性的环境因素； ii) 发现允许表型变异避免药物蓄积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，以增强耐药表型变异中抗生素的积累。鉴于当前的抗生素耐药性危机，实现这些目标非常及时：为了对抗病原微生物，我们迫切需要使药物在群体内的所有细胞中以生长抑制水平积累。