J Heart Lung Transplant. 2024 Apr 25:S1053-2498(24)01566-3. doi: 10.1016/j.healun.2024.04.005. Online ahead of print.

ABSTRACT

BACKGROUND: Inconsistent data exists regarding the risk factors for bronchoalveolar lavage (BAL) positivity in lung donors, the incidence of donor-derived infections (DDI), and the effect of BAL positivity on lung transplant (LuTx) recipients' outcome.

METHODS: A retrospective analysis was conducted on consecutive LuTx at a single center from January 2016 to December 2022. Donors' data, including characteristics, graft function and BAL samples were collected pre-procurement. Recipients underwent BAL before LuTx and about the 3rd, 7th and 14th day after LuTx. A DDI was defined as BAL positivity (bacterial growth ≥104 colony forming units) for identical bacterial species between donor and recipient. Recipients' pre-operative characteristics, intra-operative management, and post-operative outcomes were assessed. Two recipient cohorts were identified based on lung colonization status before undergoing LuTx.

RESULTS: Out of 188 LuTx procedures performed, 169 were analyzed. Thirty-six percent of donors' BAL tested positive. Donors' characteristics and graft function at procurement were not associated with BAL positivity. Fourteen DDI were detected accounting for 23% of recipients receiving a graft with a positive BAL. Only among uncolonized recipients, receiving a graft with positive BAL is associated with higher likelihood of requiring invasive ventilation at 72 hours after LuTx on higher positive end-expiratory pressure levels having lower PaO2/FiO2, prolonged duration of mechanical ventilation and longer ICU stay. No difference in hospital length of stay was observed.

CONCLUSIONS: Receiving a graft with a positive BAL, which is poorly predicted by donors' characteristics, carries the risk of developing a DDI and is associated to a worse early graft function among uncolonized recipients.

PMID:38677352 | DOI:10.1016/j.healun.2024.04.005

Diagn Microbiol Infect Dis. 2024 Apr 26;109(3):116321. doi: 10.1016/j.diagmicrobio.2024.116321. Online ahead of print.

ABSTRACT

Cystic fibrosis patients' lungs are chronically colonized by multiple microbial species capable of forming biofilms. This study aimed to characterize the polymicrobial biofilm formed by Candida spp. and S. aureus, co-isolated from sputum samples of cystic fibrosis patients regarding microbial density, metabolic activity, and structure. 67 samples from 28 patients were collected with a 96% alteration rate. 34% showed alterations by both Candida spp. and Gram-positive bacteria, predominantly Candida spp. and S. aureus in 77% of cases, accounting for 6 associations. Biofilm biomass was quantified using the crystal violet assay, and metabolic activity was assessed using the MTT reduction assay. Scanning electron microscopy analyzed the C. tropicalis/S. aureus24 biofilm architecture. Candida spp. isolates demonstrated the ability to form mixed biofilms with S. aureus. The C. tropicalis/S. aureus24 association exhibited the highest production of biofilm and metabolic activity, along with the C. albicans17/C. rugosa/S. aureus7 in both single and mixed biofilms.

PMID:38677054 | DOI:10.1016/j.diagmicrobio.2024.116321

Tuberk Toraks. 2024 Mar;72(1):9-15. doi: 10.5578/tt.202401811.

ABSTRACT

INTRODUCTION: Bronchiectasis is a chronic inflammatory lung disease and patients may occasionally experience acute exacerbations. Our study aims to determine the relationship between exacerbation periods and HALP (hemoglobin, albumin, lymphocyte, platelet) scores in patients with bronchiectasis.

MATERIALS AND METHODS: Adult patients diagnosed with bronchiectasis and followed up in our clinic between 02.2020-12.2022 were retrospectively evaluated. After the examinations, the effect of bronchiectasis exacerbation on the HALP score was investigated.

RESULT: A total of 84 patients diagnosed with non-cystic fibrosis bronchiectasis were included in our study. 42 of the patients were male (50%), and 42 were female. The average age of all patients was 52.37 ± 16.2. 35 patients (41.7%) were in the exacerbation period, and 49 patients (58.3%) were in the stable period. The median values of leukocytes, neutrophils, and C-reactive protein (CRP) were significantly higher in patients during the exacerbation period compared to the stable period (respectively p= 0.00, p= 0.00, p= 0.00). The average values of FEV1% and FVC% in patients during the exacerbation period were significantly lower compared to the stable period (p= 0.03, p= 0.00, respectively). The HALP score was significantly lower in patients during the exacerbation period compared to the stable period (p= 0.00). A significant negative correlation was found between the HALP score and leukocytes, neutrophils, and CRP (p= 0.00, p= 0.00, p= 0.00, respectively). Also, a significant positive correlation was found between the HALP score and FEV1% and FVC% (p= 0.00, p= 0.00, respectively).

CONCLUSIONS: Our study revealed that the HALP score is associated with infectious and pulmonary functional parameters in bronchiectasis patients in the exacerbation period. We propose that the HALP score could serve as a valuable biomarker during exacerbations.

PMID:38676590 | DOI:10.5578/tt.202401811

Med Chem. 2024 Apr 26. doi: 10.2174/0115734064300678240408084822. Online ahead of print.

ABSTRACT

BACKGROUND: Cathepsin G (CatG) is a cationic serine protease with a wide substrate specificity. CatG has been reported to play a role in several pathologies, including rheumatoid arthritis, ischemic reperfusion injury, acute respiratory distress syndrome, and cystic fibrosis, among others.

OBJECTIVE: We aim to develop a new class of CatG inhibitors and evaluate their potency and selectivity against a series of serine proteases.

METHODS: We exploited chemical synthesis as well as chromogenic substrate hydrolysis assays to construct and evaluate the new inhibitors.

RESULTS: In this communication, we report on a new class of CatG inhibitors of 4H-3,1-benzoxazin- 4-one derivatives. We constructed a small library of seven substituted 4H-3,1-benzoxazin-4-one derivatives and identified their inhibition potential against CatG. Five molecules were identified as CatG inhibitors with values of 0.84-5.5 μM. Inhibitor 2 was the most potent, with an IC50 of 0.84 ± 0.11 μM and significant selectivity over representative serine proteases of thrombin, factor XIa, factor XIIIa, and kallikrein.

CONCLUSION: Thus, we propose this inhibitor as a lead molecule to guide subsequent efforts to develop clinically relevant potent and selective CatG inhibitors for use as anti-inflammatory agents.

PMID:38676528 | DOI:10.2174/0115734064300678240408084822

Viruses. 2024 Apr 22;16(4):651. doi: 10.3390/v16040651.

ABSTRACT

Most repurposed drugs have proved ineffective for treating COVID-19. We evaluated median effective and toxic concentrations (EC50, CC50) of 49 drugs, mostly from previous clinical trials, in Vero cells. Ratios of reported unbound peak plasma concentrations, (Cmax)/EC50, were used to predict the potential in vivo efficacy. The 20 drugs with the highest ratios were retested in human Calu-3 and Caco-2 cells, and their CC50 was determined in an expanded panel of cell lines. Many of the 20 drugs with the highest ratios were inactive in human Calu-3 and Caco-2 cells. Antivirals effective in controlled clinical trials had unbound Cmax/EC50 ≥ 6.8 in Calu-3 or Caco-2 cells. EC50 of nucleoside analogs were cell dependent. This approach and earlier availability of more relevant cultures could have reduced the number of unwarranted clinical trials.

PMID:38675992 | DOI:10.3390/v16040651

Vaccines (Basel). 2024 Apr 9;12(4):398. doi: 10.3390/vaccines12040398.

ABSTRACT

Burkholderia cepacia complex infections remain life-threatening to cystic fibrosis patients, and due to the limited eradication efficiency of current treatments, novel antimicrobial therapies are urgently needed. Surface proteins are among the best targets to develop new therapeutic strategies since they are exposed to the host's immune system. A surface-shaving approach was performed using Burkholderia cenocepacia J2315 to quantitatively compare the relative abundance of surface-exposed proteins (SEPs) expressed by the bacterium when grown under aerobic and microaerophilic conditions. After trypsin incubation of live bacteria and identification of resulting peptides by liquid chromatography coupled with mass spectrometry, a total of 461 proteins with ≥2 unique peptides were identified. Bioinformatics analyses revealed a total of 53 proteins predicted as localized at the outer membrane (OM) or extracellularly (E). Additionally, 37 proteins were predicted as moonlight proteins with OM or E secondary localization. B-cell linear epitope bioinformatics analysis of the proteins predicted to be OM and E-localized revealed 71 SEP moieties with predicted immunogenic epitopes. The protegenicity higher scores of proteins BCAM2761, BCAS0104, BCAL0151, and BCAL0849 point out these proteins as the best antigens for vaccine development. Additionally, 10 of the OM proteins also presented a high probability of playing important roles in adhesion to host cells, making them potential targets for passive immunotherapeutic approaches. The immunoreactivity of three of the OM proteins identified was experimentally demonstrated using serum samples from cystic fibrosis patients, validating our strategy for identifying immunoreactive moieties from surface-exposed proteins of potential interest for future immunotherapies development.

PMID:38675780 | DOI:10.3390/vaccines12040398

Pharmaceutics. 2024 Mar 22;16(4):436. doi: 10.3390/pharmaceutics16040436.

ABSTRACT

Polyelectrolyte-drug complexes are interesting alternatives to improve unfavorable drug properties. Vancomycin (VAN) is an antimicrobial used in the treatment of methicillin-resistant Staphylococcus aureus pulmonary infections in patients with cystic fibrosis. It is generally administered intravenously with a high incidence of adverse side effects, which could be reduced by intrapulmonary administration. Currently, there are no commercially available inhalable formulations containing VAN. Thus, the present work focuses on the preparation and characterization of an ionic complex between hyaluronic acid (HA) and VAN with potential use in inhalable formulations. A particulate-solid HA-VAN25 complex was obtained by spray drying from an aqueous dispersion. FTIR spectroscopy and thermal analysis confirmed the ionic interaction between HA and VAN, while an amorphous diffraction pattern was observed by X-ray. The powder density, geometric size and morphology showed the suitable aerosolization and aerodynamic performance of the powder, indicating its capability of reaching the deep lung. An in vitro extended-release profile of VAN from the complex was obtained, exceeding 24 h. Microbiological assays against methicillin-resistant and -sensitive reference strains of Staphylococcus aureus showed that VAN preserves its antibacterial efficacy. In conclusion, HA-VAN25 exhibited interesting properties for the development of inhalable formulations with potential efficacy and safety advantages over conventional treatment.

PMID:38675098 | DOI:10.3390/pharmaceutics16040436

Microorganisms. 2024 Apr 16;12(4):801. doi: 10.3390/microorganisms12040801.

ABSTRACT

Pseudomonas aeruginosa contributes to frequent, persistent, and, often, polymicrobial respiratory tract infections for individuals with cystic fibrosis (CF). Chronic CF infections lead to bronchiectasis and a shortened lifespan. P. aeruginosa expresses numerous adhesins, including lectins known to bind the epithelial cell and mucin glycoconjugates. Blocking carbohydrate-mediated host-pathogen and intra-biofilm interactions critical to the initiation and perpetuation of colonization offer promise as anti-infective treatment strategies. To inform anti-adhesion therapies, we profiled the monosaccharide binding of P. aeruginosa from CF and non-CF sources, and assessed whether specific bacterial phenotypic characteristics affected carbohydrate-binding patterns. Focusing at the cellular level, microscopic and spectrofluorometric tools permitted the solution-phase analysis of P. aeruginosa binding to a panel of fluorescent glycopolymers possessing distinct pendant monosaccharides. All P. aeruginosa demonstrated significant binding to glycopolymers specific for α-D-galactose, β-D-N-acetylgalactosamine, and β-D-galactose-3-sulfate. In each culture, a small subpopulation accounted for the binding. The carbohydrate anomeric configuration and sulfate ester presence markedly influenced binding. While this opportunistic pathogen from CF hosts presented with various colony morphologies and physiological activities, no phenotypic, physiological, or structural feature predicted enhanced or diminished monosaccharide binding. Important to anti-adhesive therapeutic strategies, these findings suggest that, regardless of phenotype or clinical source, P. aeruginosa maintain a small subpopulation that may readily associate with specific configurations of specific monosaccharides. This report provides insights into whole-cell P. aeruginosa carbohydrate-binding profiles and into the context within which successful anti-adhesive and/or anti-virulence anti-infective agents for CF must contend.

PMID:38674745 | DOI:10.3390/microorganisms12040801

Microorganisms. 2024 Apr 3;12(4):732. doi: 10.3390/microorganisms12040732.

ABSTRACT

Growth environment greatly alters many facets of pathogen physiology, including pathogenesis and antimicrobial tolerance. The importance of host-mimicking environments for attaining an accurate picture of pathogen behaviour is widely recognised. Whilst this recognition has translated into the extensive development of artificial cystic fibrosis (CF) sputum medium, attempts to mimic the growth environment in other respiratory disease states have been completely neglected. The composition of the airway surface liquid (ASL) in different pulmonary diseases is far less well characterised than CF sputum, making it very difficult for researchers to model these infection environments. In this review, we discuss the components of human ASL, how different lung pathologies affect ASL composition, and how different pathogens interact with these components. This will provide researchers interested in mimicking different respiratory environments with the information necessary to design a host-mimicking medium, allowing for better understanding of how to treat pathogens causing infection in these environments.

PMID:38674677 | DOI:10.3390/microorganisms12040732

Int J Mol Sci. 2024 Apr 16;25(8):4400. doi: 10.3390/ijms25084400.

ABSTRACT

Antimicrobial resistance is a silent pandemic harming human health, and Pseudomonas aeruginosa is the most common bacterium responsible for chronic pulmonary and eye infections. Antimicrobial peptides (AMPs) represent promising alternatives to conventional antibiotics. In this review, the in vitro/in vivo activities of the frog skin-derived AMP Esc(1-21) are shown. Esc(1-21) rapidly kills both the planktonic and sessile forms of P. aeruginosa and stimulates migration of epithelial cells, likely favoring repair of damaged tissue. However, to undertake preclinical studies, some drawbacks of AMPs (cytotoxicity, poor biostability, and limited delivery to the target site) must be overcome. For this purpose, the stereochemistry of two amino acids of Esc(1-21) was changed to obtain the diastereomer Esc(1-21)-1c, which is more stable, less cytotoxic, and more efficient in treating P. aeruginosa-induced lung and cornea infections in mouse models. Incorporation of these peptides (Esc peptides) into nanoparticles or immobilization to a medical device (contact lens) was revealed to be an effective strategy to ameliorate and/or to prolong the peptides' antimicrobial efficacy. Overall, these data make Esc peptides encouraging candidates for novel multifunctional drugs to treat lung pathology especially in patients with cystic fibrosis and eye dysfunctions, characterized by both tissue injury and bacterial infection.

PMID:38673985 | DOI:10.3390/ijms25084400

Int J Mol Sci. 2024 Apr 12;25(8):4265. doi: 10.3390/ijms25084265.

ABSTRACT

Neutrophil elastase (NE) is taken up by macrophages, retains intracellular protease activity, and induces a pro-inflammatory phenotype. However, the mechanism of NE-induced pro-inflammatory polarization of macrophages is not well understood. We hypothesized that intracellular NE degrades histone deacetylases (HDAC) and Sirtuins, disrupting the balance of lysine acetylation and deacetylation and resulting in nuclear to cytoplasmic translocation of a major alarmin, High Mobility Group Box 1 (HMGB1), a pro-inflammatory response in macrophages. Human blood monocytes were obtained from healthy donors or from subjects with cystic fibrosis (CF) or chronic obstructive pulmonary disease (COPD). Monocytes were differentiated into blood monocyte derived macrophages (BMDMs) in vitro. Human BMDMs were exposed to NE or control vehicle, and the abundance of HDACs and Sirtuins was determined by Western blotting of total cell lysates or nuclear extracts or determined by ELISA. HDAC, Sirtuin, and Histone acetyltransferase (HAT) activities were measured. NE degraded most HDACs and Sirtuin (Sirt)1, resulting in decreased HDAC and sirtuin activities, with minimal change in HAT activity. We then evaluated whether the NE-induced loss of Sirt activity or loss of HDAC activities would alter the cellular localization of HMGB1. NE treatment or treatment with Trichostatin A (TSA), a global HDAC inhibitor, both increased HMGB1 translocation from the nucleus to the cytoplasm, consistent with HMGB1 activation. NE significantly degraded Class I and II HDAC family members and Sirt 1, which shifted BMDMs to a pro-inflammatory phenotype.

PMID:38673851 | DOI:10.3390/ijms25084265

Int J Mol Sci. 2024 Apr 10;25(8):4190. doi: 10.3390/ijms25084190.

ABSTRACT

Solute carrier family 26 member 4 (SLC26A4) is a member of the SLC26A transporter family and is expressed in various tissues, including the airway epithelium, kidney, thyroid, and tumors. It transports various ions, including bicarbonate, chloride, iodine, and oxalate. As a multiple-ion transporter, SLC26A4 is involved in the maintenance of hearing function, renal function, blood pressure, and hormone and pH regulation. In this review, we have summarized the various functions of SLC26A4 in multiple tissues and organs. Moreover, the relationships between SLC26A4 and other channels, such as cystic fibrosis transmembrane conductance regulator, epithelial sodium channel, and sodium chloride cotransporter, are highlighted. Although the modulation of SLC26A4 is critical for recovery from malfunctions of various organs, development of specific inducers or agonists of SLC26A4 remains challenging. This review contributes to providing a better understanding of the role of SLC26A4 and development of therapeutic approaches for the SLC26A4-associated hearing loss and SLC26A4-related dysfunction of various organs.

PMID:38673775 | DOI:10.3390/ijms25084190

J Clin Med. 2024 Apr 19;13(8):2390. doi: 10.3390/jcm13082390.

ABSTRACT

Extracellular traps made by neutrophils (NETs) and other leukocytes such as macrophages and eosinophils have a key role in the initial immune response to infection but are highly inflammatory and may contribute to tissue damage. They are particularly relevant to lung disease, with the pulmonary anatomy facilitating their ability to fully extend into the airways/alveolar space. There has been a rapid expansion in the number of published studies demonstrating their role in a variety of important respiratory diseases including chronic obstructive pulmonary disease, cystic fibrosis, bronchiectasis, asthma, pneumonia, COVID-19, rhinosinusitis, interstitial lung disease and lung cancer. The expression of NETs and other traps is a specific process, and diagnostic tests need to differentiate them from other inflammatory pathways/causes of cell death that are also characterised by the presence of extracellular DNA. The specific targeting of this pathway by relevant therapeutics may have significant clinical benefit; however, current clinical trials/evidence are at a very early stage. This review will provide a broad overview of the role of NETs and their possible treatment in respiratory disease.

PMID:38673662 | DOI:10.3390/jcm13082390

Biomedicines. 2024 Apr 13;12(4):862. doi: 10.3390/biomedicines12040862.

ABSTRACT

This study reports the complication and disease recurrence rates for ileocecal resection for pediatric and adult Crohn's disease (CD) and identifies perioperative risk factors for these adverse outcomes in the two groups. Patients who underwent ileocecal resection for CD in a tertiary hospital in Italy (2010-2021) were included. Risk factors for postoperative complications and clinical and surgical disease recurrences were investigated with multivariate models. A total of 96 patients were included (children, 25%). There were no intraoperative complications. Thirty-one (32.3%) patients experienced 35 (36.5%) postoperative complications, and five (5.2%) were severe (Clavien-Dindo III-IV-V), with no intergroup difference for either overall postoperative complication rate (p = 0.257) or severe postoperative complication rate (p = 0.097). Most of these (77.1%) occurred within 30 days after surgery, especially in adults (p = 0.013). The multivariate analysis did not show risk factors for postoperative complications. Clinical and surgical recurrence rates after 5 years were 46.8% and 14.6%, respectively, with no intergroup rate differences. Clinical disease recurrence was positively correlated with previous abdominal surgery (p = 0.047) and negatively correlated with preoperative Hb levels (p = 0.046). A positive correlation was found between perianal disease and both clinical (p = 0.045) and surgical disease recurrences (p = 0.045). Urgent surgery was positively associated with surgical disease recurrence (p = 0.045). Notably, no children underwent urgent surgery in this study. In conclusion, the risk of postoperative complications among CD patients receiving ileocecal resection remains high, but most of them are nonserious. Some factors, such as urgent surgery, may increase the risk of disease recurrences.

PMID:38672216 | DOI:10.3390/biomedicines12040862

Sci Rep. 2024 Apr 26;14(1):9664. doi: 10.1038/s41598-024-60389-9.

ABSTRACT

The nasal potential difference test (nPD) is an electrophysiological measurement which is altered in patients and animal models with cystic fibrosis (CF). Because protocols and outcomes vary substantially between laboratories, there are concerns over its validity and precision. We performed a systematic literature review (SR) of the nPD to answer the following review questions: A. Is the nasal potential difference similarly affected in CF patients and animal models?", and B. "Is the nPD in human patients and animal models of CF similarly affected by various changes in the experimental set-up?". The review protocol was preregistered on PROSPERO (CRD42021236047). We searched PubMed and Embase with comprehensive search strings. Two independent reviewers screened all references for inclusion and extracted all data. Included were studies about CF which described in vivo nPD measurements in separate CF and control groups. Risk of bias was assessed, and three meta-analyses were performed. We included 130 references describing nPD values for CF and control subjects, which confirmed substantial variation in the experimental design and nPD outcome between groups. The meta-analyses showed a clear difference in baseline nPD values between CF and control subjects, both in animals and in humans. However, baseline nPD values were, on average, lower in animal than in human studies. Reporting of experimental details was poor for both animal and human studies, and urgently needs to improve to ensure reproducibility of experiments within and between species.

PMID:38671057 | DOI:10.1038/s41598-024-60389-9

Am J Respir Crit Care Med. 2024 Apr 26. doi: 10.1164/rccm.202307-1165OC. Online ahead of print.

ABSTRACT

RATIONALE: Nontuberculous mycobacteria (NTM) are prevalent among patients with bronchiectasis. However, the long-term natural history of patients with NTM and bronchiectasis is not well described.

OBJECTIVE: To assess the impact of NTM on 5-year clinical outcomes and mortality in patients with bronchiectasis.

METHODS: Patients in the United States Bronchiectasis and Nontuberculous Mycobacteria Research Registry with ≥5 years of follow-up were eligible. Data were collected for all-cause mortality, lung function, exacerbations, hospitalizations, and disease severity. Outcomes were compared between patients with and without NTM at baseline. Mortality was assessed using Cox proportional hazards models and the log-rank test.

MEASUREMENTS AND MAIN RESULTS: In total, 2,634 patients were included: 1,549 (58.8%) with and 1,085 (41.2%) without NTM at baseline. All-cause mortality (95% confidence interval) at Year 5 was 12.1% (10.5%, 13.7%) overall, 12.6% (10.5%, 14.8%) in patients with NTM, and 11.5% (9.0%, 13.9%) in patients without NTM. Independent predictors of 5-year mortality were baseline forced expiratory volume in 1 second % predicted, age, hospitalization within 2 years before baseline, body mass index, and gender (all p<0.01). The probabilities of acquiring NTM or Pseudomonas aeruginosa were approximately 4% and 3% per year, respectively. Spirometry, exacerbations, and hospitalizations were similar irrespective of NTM status, except that annual exacerbations were lower in patients with NTM (p<0.05).

CONCLUSIONS: Outcomes including exacerbations, hospitalizations, rate of loss of lung function, and mortality rate were similar across 5 years in patients with bronchiectasis with or without NTM.

PMID:38668710 | DOI:10.1164/rccm.202307-1165OC

Antibiotics (Basel). 2024 Apr 5;13(4):330. doi: 10.3390/antibiotics13040330.

ABSTRACT

Stenotrophomonas maltophilia is an opportunistic pathogen that produces respiratory infections in immunosuppressed and cystic fibrosis patients. The therapeutic options to treat S. maltophilia infections are limited since it exhibits resistance to a wide variety of antibiotics such as β-lactams, aminoglycosides, tetracyclines, cephalosporins, macrolides, fluoroquinolones, or carbapenems. The antibiotic combination trimethoprim/sulfamethoxazole (SXT) is the treatment of choice to combat infections caused by S. maltophilia, while ceftazidime, ciprofloxacin, or tobramycin are used in most SXT-resistant infections. In the current study, experimental evolution and whole-genome sequencing (WGS) were used to examine the evolutionary trajectories of S. maltophilia towards resistance against tobramycin, ciprofloxacin, and SXT. The genetic changes underlying antibiotic resistance, as well as the evolutionary trajectories toward that resistance, were determined. Our results determine that genomic changes in the efflux pump regulatory genes smeT and soxR are essential to confer resistance to ciprofloxacin, and the mutation in the rplA gene is significant in the resistance to tobramycin. We identified mutations in folP and the efflux pump regulator smeRV as the basis of SXT resistance. Detailed and reliable knowledge of ciprofloxacin, tobramycin, and SXT resistance is essential for safe and effective use in clinical settings. Herein, we were able to prove once again the extraordinary ability that S. maltophilia has to acquire resistance and the importance of looking for alternatives to combat this resistance.

PMID:38667006 | DOI:10.3390/antibiotics13040330

Front Pharmacol. 2024 Apr 11;15:1370676. doi: 10.3389/fphar.2024.1370676. eCollection 2024.

ABSTRACT

Cystic fibrosis (CF) is a monogenetic disease caused by the mutation of CFTR, a cAMP-regulated Cl- channel expressing at the apical plasma membrane (PM) of epithelia. ∆F508-CFTR, the most common mutant in CF, fails to reach the PM due to its misfolding and premature degradation at the endoplasmic reticulum (ER). Recently, CFTR modulators have been developed to correct CFTR abnormalities, with some being used as therapeutic agents for CF treatment. One notable example is Trikafta, a triple combination of CFTR modulators (TEZ/ELX/IVA), which significantly enhances the functionality of ΔF508-CFTR on the PM. However, there's room for improvement in its therapeutic effectiveness since TEZ/ELX/IVA doesn't fully stabilize ΔF508-CFTR on the PM. To discover new CFTR modulators, we conducted a virtual screening of approximately 4.3 million compounds based on the chemical structures of existing CFTR modulators. This effort led us to identify a novel CFTR ligand named FR3. Unlike clinically available CFTR modulators, FR3 appears to operate through a distinct mechanism of action. FR3 enhances the functional expression of ΔF508-CFTR on the apical PM in airway epithelial cell lines by stabilizing NBD1. Notably, FR3 counteracted the degradation of mature ΔF508-CFTR, which still occurs despite the presence of TEZ/ELX/IVA. Furthermore, FR3 corrected the defective PM expression of a misfolded ABCB1 mutant. Therefore, FR3 may be a potential lead compound for addressing diseases resulting from the misfolding of ABC transporters.

PMID:38666024 | PMC:PMC11043560 | DOI:10.3389/fphar.2024.1370676

Frontline Gastroenterol. 2024 Jan 6;15(3):222-227. doi: 10.1136/flgastro-2023-102533. eCollection 2024 May.

ABSTRACT

OBJECTIVE: Constipation and distal intestinal obstruction syndrome (DIOS) are common gastrointestinal manifestations of cystic fibrosis (CF). The primary aim was to describe the characteristics of constipation and DIOS hospitalisations in a paediatric and adult CF service over a 12-year period. The secondary aims were to determine the proportion of constipation and DIOS presentations which met the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) CF Working Group definitions and to describe management strategies of both conditions.

METHOD: A retrospective study of children and adults with CF who were admitted with a primary diagnosis of constipation or DIOS between 1 January 2011 and 31 December 2022. ESPGHAN definitions for constipation and DIOS were retrospectively applied to all admissions to determine if the primary medical diagnosis met ESPGHAN criteria.

RESULTS: During the 12-year study period, 42 hospitalisations for constipation were recorded in 19 patients, and 33 hospitalisations for DIOS were recorded in 23 patients. 88.10% of constipation episodes met ESPGHAN definitions, compared with 3.0% of DIOS episodes. Constipation and DIOS were primarily treated with polyethylene glycol (PEG). The use of sodium amidotrizoate meglumine enemas was significantly higher in the DIOS group (p=0.045). Those admitted with DIOS were significantly less likely to be recommended a weaning dose of PEG (p=0.018).

CONCLUSION: Children and adults with CF are more commonly admitted for the management of constipation than DIOS. There is considerable variation in diagnostic and therapeutic practice, and this study highlights the need to enhance the translation and adoption of existing best-practice guidelines.

PMID:38665789 | PMC:PMC11042455 | DOI:10.1136/flgastro-2023-102533

Front Pediatr. 2024 Apr 11;12:1387171. doi: 10.3389/fped.2024.1387171. eCollection 2024.

ABSTRACT

INTRODUCTION: Meconium ileus (MI) is a life-threatening obstruction of the intestines affecting ∼15% of newborns with cystic fibrosis (CF). Current medical treatments for MI often fail, requiring surgical intervention. MI typically occurs in newborns with pancreatic insufficiency from CF. Meconium contains mucin glycoprotein, a potential substrate for pancreatic enzymes or mucolytics. Our study aim was to determine whether pancreatic enzymes in combination with mucolytic treatments dissolve obstructive meconium using the CF pig model.

METHODS: We collected meconium from CF pigs at birth and submerged it in solutions with and without pancreatic enzymes, including normal saline, 7% hypertonic saline, and the reducing agents N-acetylcysteine (NAC) and dithiothreitol (DTT). We digested meconium at 37 °C with agitation, and measured meconium pigment release by spectrophotometry and residual meconium solids by filtration.

RESULTS AND DISCUSSION: In CF pigs, meconium appeared as a solid pigmented mass obstructing the ileum. Meconium microscopically contained mucus glycoprotein, cellular debris, and bile pigments. Meconium fragments released pigments with maximal absorption at 405 nm after submersion in saline over approximately 8 h. Pancreatic enzymes significantly increased pigment release and decreased residual meconium solids. DTT did not improve meconium digestion and the acidic reducing agent NAC worsened digestion. Pancreatic enzymes digested CF meconium best at neutral pH in isotonic saline. We conclude that pancreatic enzymes digest obstructive meconium from CF pigs, while hydrating or reducing agents alone were less effective. This work suggests a potential role for pancreatic enzymes in relieving obstruction due to MI in newborns with CF.

PMID:38665380 | PMC:PMC11043547 | DOI:10.3389/fped.2024.1387171