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Burkholderia cenocepacia antimicrobial resistance and physiology at acidic pH in the cystic fibrosis nutritional environment Morales Duran, Laura Daniela


Burkholderia cenocepacia is an opportunistic pathogen correlated with increased disease severity and mortality in cystic fibrosis (CF) patients. It is resistant to a wide range of disinfectants and antibiotics, and no standard treatment is available to eradicate these infections. Previous analysis of CF sputum showed elevated levels of zinc and iron ions and lower pH (2.9-6.5), compared to healthy individuals. Burkholderia species are abundant in acidic soils and some are heavy-metal resistant. B. cenocepacia grows at acidic pH (~3.5) and persists in acid compartments of amoebas and macrophages. We aimed to understand the impact of acidic pH and increased zinc and iron concentrations on B. cenocepacia physiology and antibiotic resistance. We modified a synthetic cystic fibrosis sputum media (SCFM) to represent the acidic pH and high zinc and iron concentrations found in CF sputum (SCFM-FeZn). We found that elevated iron and acidic pH increased B. cenocepacia growth rate, and more strikingly decreased susceptibility to antimicrobials used clinically to treat CF infections. We studied B. cenocepacia internal pH homeostasis and found that it maintains a neutral internal pH when exposed to mildly acidic external pH (5.50). We also assessed the effect of B. cenocepacia growth on the SCFM external pH. B. cenocepacia cultured at pH 6.8, maintained an external pH of ~6.5, and when culture at pH 5.5, it increased to 6.5. Using comparative transcriptomics and metabolomics analysis, we identified 990 differentially expressed genes, and 23 differentially abundant metabolites in supernatants at acidic compared to neutral pH. Some of these genes and metabolites were involved in aromatic amino acid metabolism. One gene (trpE) with increased expression encodes an enzyme in the tryptophan biosynthesis pathway. A trpE deletion strain showed decreased growth in SCFM-FeZn and was a tryptophan auxotroph. All in all, this work demonstrates that acidic pH in the sputum environment modulates B. cenocepacia antimicrobial susceptibility and triggers molecular mechanisms associated with pathogenicity and virulence. Understanding B. cenocepacia physiology and antimicrobial susceptibility in the CF nutritional environment could help improve susceptibility testing in the clinical environment, and pave the way to design new antimicrobial therapies against B. cenocepacia infections.

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