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Entropically driven aggregation of bacteria by host polymers promotes antibiotic tolerance in Pseudomonas aeruginosa.

ABSTRACT: Bacteria causing chronic infections are generally observed living in cell aggregates suspended in polymer-rich host secretions, and bacterial phenotypes induced by aggregated growth may be key factors in chronic infection pathogenesis. Bacterial aggregation is commonly thought of as a consequence of biofilm formation; however the mechanisms producing aggregation in vivo remain unclear. Here we show that polymers that are abundant at chronic infection sites cause bacteria to aggregate by the depletion aggregation mechanism, which does not require biofilm formation functions. Depletion aggregation is mediated by entropic forces between uncharged or like-charged polymers and particles (e.g., bacteria). Our experiments also indicate that depletion aggregation of bacteria induces marked antibiotic tolerance that was dependent on the SOS response, a stress response activated by genotoxic stress. These findings raise the possibility that targeting conditions that promote depletion aggregation or mechanisms of depletion-mediated tolerance could lead to new therapeutic approaches to combat chronic bacterial infections.

SUBMITTER: Secor PR

PROVIDER: S-EPMC6196481 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Entropically driven aggregation of bacteria by host polymers promotes antibiotic tolerance in <i>Pseudomonas aeruginosa</i>.

Secor Patrick R PR Michaels Lia A LA Ratjen Anina A Jennings Laura K LK Singh Pradeep K PK

Proceedings of the National Academy of Sciences of the United States of America 20181001 42

Bacteria causing chronic infections are generally observed living in cell aggregates suspended in polymer-rich host secretions, and bacterial phenotypes induced by aggregated growth may be key factors in chronic infection pathogenesis. Bacterial aggregation is commonly thought of as a consequence of biofilm formation; however the mechanisms producing aggregation in vivo remain unclear. Here we show that polymers that are abundant at chronic infection sites cause bacteria to aggregate by the depl ...[more]

PMID: 30275316

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Project description:Chronic infections with Pseudomonas aeruginosa are a leading cause of morbidity and mortality in persons with cystic fibrosis (pwCF). P. aeruginosa persists in the CF lung by utilizing adaptation strategies to cause infection, including altering the expression of metabolic genes to acquire nutrients that are abundant in the CF airway. Glycerol in the airway is imported and metabolized by the glp regulon, which is under the control of the GlpR repressor. It has been shown that the loss of GlpR results in increased biofilm development in P. aeruginosa CF isolate compared to a wound isolate. Based on the increased biofilm phenotype observed and because biofilms are associated with increased antibiotic tolerance, we questioned whether GlpR plays a role in mediating antibiotic resistance of P. aeruginosa. We measured tobramycin tolerance in wild-type and glpR-defective P. aeruginosa isolates from the CF airway (FRD1) and a wound (PAO1). Cultures were grown in lysogeny broth or synthetic cystic fibrosis sputum consisting of the base formula of primarily amino acids (SCFM1) or supplemented with mucins and DNA (SCFM2), with dose-dependent concentrations of tobramycin. We tested the impact of a glpR mutation on P. aeruginosa adherence on bronchial epithelial cells from pwCF (CFBE) in the presence of tobramycin. CFBE cells were inoculated at an MOI of ~1:20 for 1 hour, given fresh apical media for 5 more hours, then apical and basal media was replaced with media containing 20 µg/ml tobramycin. We measured colony forming units (CFUs) and lactate dehydrogenase (LDH) release for cytotoxicity. Loss of glpR increased tolerance to tobramycin in both the PAO1 and FRD1 backgrounds in vitro at a concentration of 0.625 µg/mL in lysogeny broth and SCFM1. On both CFBE’s and 16HBE’s, the antibiotic resistance phenotype was more prominent in FRD1 glpR with a 2-log increase in viable bacteria when grown on cells and treated with 20 ug/ml tobramycin. However, changes in cytotoxicity where not observed between wildtype and GlpR mutants as LDH measurements were not significantly different. Our results indicate that GlpR may regulate antibiotic tolerance, in addition to biofilm development and glycerol metabolism. Additional studies are necessary to determine the mechanism of how GlpR modulates biofilm development and antibiotic tolerance.

Dataset Information

Entropically driven aggregation of bacteria by host polymers promotes antibiotic tolerance in Pseudomonas aeruginosa.

Publications

Entropically driven aggregation of bacteria by host polymers promotes antibiotic tolerance in <i>Pseudomonas aeruginosa</i>.

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