Disrupting folate metabolism alters the capacity of bacteria in exponential growth to develop persisters to antibiotics

Abstract

Bacteria can survive high doses of antibiotics through stochastic phenotypic diversification.We present initial evidence that folate metabolism could be involved with the formation of persisters. The aberrant expression of the folate enzyme gene fau seems to reduce the incidence of persisters to antibiotics. Folate impaired bacteria had a lower generation rate for persisters to both antibiotics ampicillin and ofloxacin. Persister bacteria were detectable from the outset of the exponential growth phase in the complex media. Gene expression analyses showed tentatively distinctive profiles in exponential growth at times when bacteria persisters were observed. Levels of persisters were assessed in bacteria with altered, genetically and pharmacologically, folate metabolism. This work shows that by disrupting folate biosynthesis and usage, bacterial tolerance to antibiotics seems to be diminished. Based on these findings there is a possibility that bacteriostatic antibiotics such as antifolates could have a role to play in clinical settings where the incidence of antibiotic persisters seem to drive recalcitrant infections.

Genome-Scale Metabolic Models and Machine Learning Reveal Genetic Determinants of Antibiotic Resistance in Escherichia coli and Unravel the Underlying Metabolic Adaptation Mechanisms

“…We identified folP in the trimethoprim, tetracycline, and ampicillin ML models. Folate metabolism, including THF, however, are again important for nucleotide biosynthesis and have in fact been found important for persistence in E. coli cells exposed to ampicillin ( 83 ). The production of coenzyme A (CoA) is also affected by these genes, as well as the ilvD and panD genes.…”

“…Importantly, however, we identified folP in the trimethoprim, tetracycline, and ampicillin ML models. Folate metabolism, including tetrahydrofolate (THF), however, are again important for nucleotide biosynthesis and have in fact been found important for persistence in E. coli cells exposed to ampicillin ( 83 ). Importantly, a number of additional genes affecting folate metabolism were also identified in the metabolite reproducibility analysis and flux variability analysis.…”

Molecular physiological characterization of the dynamics of persister formation inStaphylococcus aureus

“…THF was found to directly participate in crucial metabolic activities including the synthesis of nucleotide, purine and amino acids [26]. Besides, in E. coli, the overexpression of 5-formyltetrahydrofolate cyclo-ligase (Q2FZJ6 in S. aureus) promotes persister formation upon ampicillin and ofloxacin exposure [27]. In summary, this described metabolic rewiring suggests that persisters, despite being growth arrested, alter their metabolic pathways to favor energy needs and the provision of precursors for essential cellular processes in response to antimicrobial treatment.…”