DYNBIOTICS - Understanding the dynamics of antibiotics transport in individual bacteria

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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.