Advances in the Cystic Fibrosis Drug Development Pipeline

Esposito, Christine; Kamper, Martin; Trentacoste, Jessica; Galvin, Susan; Pfister, Halie; Wang, Janice

doi:10.3390/life13091835

Cited by 6 publications

(2 citation statements)

References 83 publications

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“…In conclusion, PTUs here reported could represent a new starting point for the development of new antibacterial pyrazole-based agents [ 35 , 36 , 37 , 38 ] able to counteract strains resistant to common antibiotics and consequently a new therapeutic approach for CF patients [ 39 , 40 , 41 ]. Additional studies will be necessary to identify the mechanism of action of this class of molecules.…”

Section: Discussionmentioning

confidence: 99%

New Pyrazolyl Thioureas Active against the Staphylococcus Genus

Schito,

Caviglia,

Penco

et al. 2024

Pharmaceuticals

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To meet the urgent need for new antibacterial molecules, a small library of pyrazolyl thioureas (PTUs) was designed, synthesized and tested against difficult-to-treat human pathogens. The prepared derivatives are characterized by a carboxyethyl functionality on C4 and different hydroxyalkyl chains on N1. Compounds 1a–o were first evaluated against a large panel of Gram-positive and Gram-negative pathogens. In particular, the majority of PTUs proved to be active against different species of the Staphylococcus genus, with MIC values ranging from 32 to 128 µg/mL on methicillin-resistant Staphylococcus strains, often responsible for severe pulmonary disease in cystic fibrosis patients. Time-killing experiments were also performed for the most active compounds, evidencing a bacteriostatic mechanism of action. For most active derivatives, cytotoxicity was evaluated in Vero cells, and at the tested concentrations and at the experimental exposure time of 24 h, none of the compounds analysed showed significant toxicity. In addition, favourable drug-like, pharmacokinetic and toxicity properties were predicted for all new synthesized derivatives. Overall, the collected data confirmed the PTU scaffold as a promising chemotype for the development of novel antibacterial agents active against Gram-positive multi-resistant strains frequently isolated from cystic fibrosis patients.

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Section: Discussionmentioning

confidence: 99%

New Pyrazolyl Thioureas Active against the Staphylococcus Genus

Schito,

Caviglia,

Penco

et al. 2024

Pharmaceuticals

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“…The difficulty of finding participants to obtain fresh spontaneously expectorated sputum, along with the reduction in individuals producing spontaneously expectorated sputum, primarily due to the use of HEMT ( 94 ), increases the need for accurate in vitro model systems. A 2% mucin SCFM2 in vitro model provides an effective system to supplement or replace ex vivo sputum studies.…”

Section: Discussionmentioning

confidence: 99%

Mucus polymer concentration and in vivo adaptation converge to define the antibiotic response of Pseudomonas aeruginosa during chronic lung infection

Greenwald,

Meinig,

Plott

et al. 2024

mBio

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The airway milieu of individuals with muco-obstructive airway diseases (MADs) is defined by the accumulation of dehydrated mucus due to hyperabsorption of airway surface liquid and defective mucociliary clearance. Pathological mucus becomes progressively more viscous with age and disease severity due to the concentration and overproduction of mucin and accumulation of host-derived extracellular DNA (eDNA). Respiratory mucus of MADs provides a niche for recurrent and persistent colonization by respiratory pathogens, including Pseudomonas aeruginosa , which is responsible for the majority of morbidity and mortality in MADs. Despite high concentration inhaled antibiotic therapies and the absence of antibiotic resistance, antipseudomonal treatment failure in MADs remains a significant clinical challenge. Understanding the drivers of antibiotic tolerance is essential for developing more effective treatments that eradicate persistent infections. The complex and dynamic environment of diseased airways makes it difficult to model antibiotic efficacy in vitro . We aimed to understand how mucin and eDNA concentrations, the two dominant polymers in respiratory mucus, alter the antibiotic tolerance of P. aeruginosa . Our results demonstrate that polymer concentration and molecular weight affect P. aeruginosa survival post antibiotic challenge. Polymer-driven antibiotic tolerance was not explicitly associated with reduced antibiotic diffusion. Lastly, we established a robust and standardized in vitro model for recapitulating the ex vivo antibiotic tolerance of P. aeruginosa observed in expectorated sputum across age, underlying MAD etiology, and disease severity, which revealed the inherent variability in intrinsic antibiotic tolerance of host-evolved P. aeruginosa populations. IMPORTANCE Antibiotic treatment failure in Pseudomonas aeruginosa chronic lung infections is associated with increased morbidity and mortality, illustrating the clinical challenge of bacterial infection control. Understanding the underlying infection environment, as well as the host and bacterial factors driving antibiotic tolerance and the ability to accurately recapitulate these factors in vitro , is crucial for improving antibiotic treatment outcomes. Here, we demonstrate that increasing concentration and molecular weight of mucin and host eDNA drive increased antibiotic tolerance to tobramycin. Through systematic testing and modeling, we identified a biologically relevant in vitro condition that recapitulates antibiotic tolerance observed in ex vivo treated sputum. Ultimately, this study revealed a dominant effect of in vivo evolved bacterial populations in defining inter-subject ex vivo antibiotic tolerance and establishes a robust and translatable in vitro model for therapeutic development.

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Emerging biomarkers for precision diagnosis and personalized treatment of cystic fibrosis

Addissouky,

Sayed,

Ali

et al. 2024

J Rare Dis

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Background Cystic fibrosis (CF) is a fatal genetic disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, disrupting ion transport. This results in organ damage and reduced life expectancy. Main body of the abstract Recent therapeutic advances targeting CFTR dysfunction have transformed treatment. CFTR modulator drugs directly target molecular defects underlying CF. Ivacaftor was the first approved potentiator benefiting gating mutations. Correctors like lumacaftor/ivacaftor and newer triple therapy combinations more effectively address the prevalent F508del mutation by improving CFTR processing. Gene and mRNA therapies also show promise, with preclinical studies editing CFTR in stem cell-derived epithelia and mRNA supplementation stabilizing acute exacerbations. Short conclusion Targeting CFTR dysfunction through small molecules, gene editing, and cell-based therapies represents a paradigm shift from symptom management to addressing genetic causes. Expanding access to innovative treatments across all patient subgroups may modify disease progression. While awaiting genetic cures, emerging strategies provide hope that CF outcomes can transition from early lethality to a chronic condition with an improved life expectancy and quality of life.

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Advances in the Cystic Fibrosis Drug Development Pipeline

Cited by 6 publications

References 83 publications

New Pyrazolyl Thioureas Active against the Staphylococcus Genus

New Pyrazolyl Thioureas Active against the Staphylococcus Genus

Mucus polymer concentration and in vivo adaptation converge to define the antibiotic response of Pseudomonas aeruginosa during chronic lung infection

Emerging biomarkers for precision diagnosis and personalized treatment of cystic fibrosis

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