Recipient organisationUniversity of ExeterSource-published name: University of Exeter
Funding£1.7M
PeriodJan 2024 — Dec 2028
In plain English
AI plain-English summary
Some genetically identical bacteria hoard antibiotics while their neighbours let the drugs pour in, and this project aims to stop them. This matters because a small subpopulation of bacteria can survive a course of antibiotics without inheriting any resistance genes—they simply fail to accumulate enough drug to die. This "phenotypic resistance" makes infections stubbornly recurrent, especially in ESKAPE pathogens on the WHO critical priority list. Current methods cannot track antibiotic accumulation inside single cells, so the mechanisms behind these cell-to-cell differences remain unknown. If this research succeeds, it could identify antibiotic-adjuvant combinations that force drug levels high enough in every bacterial cell to kill the whole population. That would directly address the antibiotic resistance crisis by making existing drugs work against phenotypically resistant variants, without needing new antibiotics. The project uses biophysics, omics, and mathematical modelling to find the environmental triggers and membrane transport mechanisms that create these drug-avoiding variants. This is fundamental science with a clear practical target: making antibiotics accumulate at growth-inhibitory levels in all cells, not just most of them.
View original technical description
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.
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