Combinational Effects of Specific Proton Motive Force (PMF) Dissipators and Metabolites on Re-sensitizing Bacterial Persisters to Antibiotics and the Underlying Mechanisms
DescriptionOur laboratory recently unveiled a series of bacterial physiological mechanisms that support bacterial survival under nutrient starvation conditions. We found that the bacterial tolerant sub-population actively maintains a strong proton motive force (PMF) or transmembrane electric potential in order to support a range of membrane activities even upon experiencing starvation for a prolonged period. This stress-tolerant form of bacteria, which are better known as antibiotic persisters, is hard to be eradicated and known to be responsible for causing chronic and recurrent infections. Our preliminary data also showed that suppressing the PMF of persisters can strongly re-sensitize such cells to various antibiotics. PMF suppression therefore represents an excellent antimicrobial approach that needs in-depth exploration. On the other hand, we also discovered that supplementing specific intermediate metabolites in several biosynthesis pathways to antibiotic persisters could also re-sensitize these cells to specific antibiotics without eliciting re-growth of the persisters. We hypothesize that the two approaches of PMF suppression and metabolite activation can complement each other to reduce viability of virulent and resistant bacteria in the human body, and re-sensitize the tolerant form of even resistant strains to common antibiotics. This idea has not been reported or explored in the scientific community. In this proposal, we aim to examine the key but poorly understood physiological changes in the persisters of multidrug resistant and highly virulent strains upon PMF suppression and supplementation of specific nutrients, and study how these events affect viability and antibiotic susceptibility of persisters. We plan to use carbapenem resistant, hypervirulent Klebsiella pneumoniae strains as a model organism to assess how PMF suppression induces physiological changes in persisters of this pathogenic strain, and the extent by which their ability to synthesize and export virulence factors and carbapenam-degrading enzymes is affected. In addition, the combined effect of PMF dissipation and supplementation of specific nutrient on maintenance of viability and antibiotic tolerance during stress as well as the underlying mechanisms will also be studied. Findings in this work would inform us whether we can seize the opportunity to inhibit physiological functions of resistant and virulent strains when they encounter environmental stresses, and allow us to devise novel antimicrobial drug regimens that comprise non-toxic PMF dissipators, specific metabolites and conventional antibiotics in order to provide an ultimate solution to the aggravating clinical problems of both antibiotic resistance and tolerance.
|Effective start/end date||1/01/23 → …|