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1. O-Specific Antigen-Dependent Surface Hydrophobicity Mediates Aggregate Assembly Type in Pseudomonas aeruginosa

   https://doi.org/10.1128/mBio.00860-21  

   Azimi, Sheyda; Thomas, Jacob; Cleland, Sara E.; Curtis, Jennifer E.; Goldberg, Joanna B.; Diggle, Stephen P. (August 2021, mBio)

   Trent, M. Stephen (Ed.)

   ABSTRACT Bacteria live in spatially organized aggregates during chronic infections, where they adapt to the host environment, evade immune responses, and resist therapeutic interventions. Although it is known that environmental factors such as polymers influence bacterial aggregation, it is not clear how bacterial adaptation during chronic infection impacts the formation and spatial organization of aggregates in the presence of polymers. Here, we show that in an in vitro model of cystic fibrosis (CF) containing the polymers extracellular DNA (eDNA) and mucin, O-specific antigen is a major factor determining the formation of two distinct aggregate assembly types of Pseudomonas aeruginosa due to alterations in cell surface hydrophobicity. Our findings suggest that during chronic infection, the interplay between cell surface properties and polymers in the environment may influence the formation and structure of bacterial aggregates, which would shed new light on the fitness costs and benefits of O-antigen production in environments such as CF lungs. IMPORTANCE During chronic infection, several factors contribute to the biogeography of microbial communities. Heterogeneous populations of Pseudomonas aeruginosa form aggregates in cystic fibrosis airways; however, the impact of this population heterogeneity on spatial organization and aggregate assembly is not well understood. In this study, we found that changes in O-specific antigen determine the spatial organization of P. aeruginosa cells by altering the relative cell surface hydrophobicity. This finding suggests a role for O-antigen in regulating P. aeruginosa aggregate size and shape in cystic fibrosis airways. 

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2. Virulence attenuating combination therapy: a potential multi-target synergy approach to treat Pseudomonas aeruginosa infections in cystic fibrosis patients

   https://doi.org/10.1039/c9md00566h  

   Shaw, Elana; Wuest, William M. (March 2020, RSC Medicinal Chemistry)

   The World Health Organization considers the discovery of new treatments for P. aeruginosa a top priority. Virulence attenuating combination therapy (VACT) is a pragmatic strategy to improve bacterial clearance, repurpose outmoded antibiotics, improve drug efficacy at lower doses, and reduce the evolution of resistance. In vitro and in vivo studies have shown that adding a quorum sensing inhibitor or an extracellular polymeric substance repressor to classical antibiotics synergistically improves antipseudomonal activity. This review highlights why VACT could specifically benefit cystic fibrosis patients harboring chronic P. aeruginosa infections, outlines the current landscape of synergistic combinations between virulence-targeting small-molecules and anti-pseudomonal drugs, and suggests future directions for VACT research. 

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3. Intestinal Bacteroides modulates inflammation, systemic cytokines, and microbial ecology via propionate in a mouse model of cysfibrosis

   https://doi.org/10.1128/mbio.03144-23  

   Price, Courtney E; Valls, Rebecca A; Ramsey, Alexis R; Loeven, Nicole A; Jones, Jane T; Barrack, Kaitlyn E; Schwartzman, Joseph D; Royce, Darlene B; Cramer, Robert A; Madan, Juliette C; et al (January 2024, mBio)

   Harwood, Caroline S (Ed.)

   Persons with cystic fibrosis (CF), starting in early life, show intestinal microbiome dysbiosis characterized in part by a decreasedrelative abundance of the genus Bacteroides. Bacteroides is a major producer of the intestinal short chain fatty acid propionate. Wdemonstrate here that cystic fibrosis transmembrane conductance regulator-defective (CFTR−/−) Caco-2 intestinal epithelial cellsresponsive to the anti-inflammatory effects of propionate. Furthermore, Bacteroides isolates inhibit the IL-1β-induced inflammatorresponse of CFTR−/− Caco-2 intestinal epithelial cells and do so in a propionate-dependent manner. The introduction of Bacteroisupplemented stool from infants with cystic fibrosis into the gut of CftrF508del mice results in higher propionate in the stool as wethe reduction in several systemic pro-inflammatory cytokines. Bacteroides supplementation also reduced the fecal relativeabundance of Escherichia coli, indicating a potential interaction between these two microbes, consistent with previous clinicalstudies. For a Bacteroides propionate mutant in the mouse model, pro-inflammatory cytokine KC is higher in the airway and serucompared with the wild-type (WT) strain, with no significant difference in the absolute abundance of these two strains. Takentogether, our data indicate the potential multiple roles of Bacteroides-derived propionate in the modulation of systemic and airwayinflammation and mediating the intestinal ecology of infants and children with CF. The roles of Bacteroides and the propionate itproduces may help explain the observed gut-lung axis in CF and could guide the development of probiotics to mitigate systemic aairway inflammation for persons with CF. 

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4. Heterogenous biofilm mass-transport model replicates periphery sequestration of antibiotics in Pseudomonas aeruginosa PAO1 microcolonies

   https://doi.org/10.1073/pnas.2312995120  

   Prince, Joshua; Jones, A-Andrew D (November 2023, Proceedings of the National Academy of Sciences)

   A model for antibiotic accumulation in bacterial biofilm microcolonies utilizing heterogenous porosity and attachment site profiles replicated the periphery sequestration reported in prior experimental studies onPseudomonas aeruginosa PAO1biofilm cell clusters. TheseP. aeruginosacell clusters are in vitro models of the chronicP. aeruginosainfections in cystic fibrosis patients which display recalcitrance to antibiotic treatments, leading to exacerbated morbidity and mortality. This resistance has been partially attributed to periphery sequestration, where antibiotics fail to penetrate biofilm cell clusters. The physical phenomena driving this periphery sequestration have not been definitively established. This paper introduces mathematical models to account for two proposed physical phenomena driving periphery sequestration: biofilm matrix attachment and volume-exclusion due to variable biofilm porosity. An antibiotic accumulation model which incorporated these phenomena better fit observed periphery sequestration data compared to previous models. 

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5. The Antimicrobial Peptide Gad‐1 Clears Pseudomonas aeruginosa Biofilms under Cystic Fibrosis Conditions

   https://doi.org/10.1002/cbic.202000816  

   Portelinha, Jasmin; Angeles‐Boza, Alfredo_M (February 2021, ChemBioChem)

   Abstract Bacterial infections in cystic fibrosis (CF) patients are an emerging health issue and lead to a premature death. CF is a hereditary disease that creates a thick mucus in the lungs that is prone to bacterial biofilm formation, specificallyPseudomonas aeruginosabiofilms. These biofilms are very difficult to treat because many of them have antibiotic resistance that is worsened by the presence of extracellular DNA (eDNA). eDNA helps to stabilize biofilms and can bind antimicrobial compounds to lessen their effects. The metallo‐antimicrobial peptide Gaduscidin‐1 (Gad‐1) eradicates establishedP. aeruginosabiofilms through a combination of modes of action that includes nuclease activity that can cleave eDNA in biofilms. In addition, Gad‐1 exhibits synergistic activity when used with the antibiotics kanamycin and ciprofloxacin, thus making Gad‐1 a new lead compound for the potential treatment of bacterial biofilms in CF patients. 

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