Pathogens. 2021 Apr 26;10(5):519. doi: 10.3390/pathogens10050519.

ABSTRACT

Pseudomonas aeruginosa and Aspergillus fumigatus are pathogens that are associated with deterioration of lung function, e.g., in persons with cystic fibrosis (CF). There is evidence that co-infections with these pathogens cause airway inflammation and aggravate pathology in CF lungs. Intermicrobial competition of P. aeruginosa and A. fumigatus has been described, but it is unknown how anti-fungal therapy is affected. The anti-fungal azole voriconazole (VCZ), supernatants of P. aeruginosa laboratory isolates PA14 or PAO1, or clinical isolate Pa10 independently inhibited biofilm metabolism of A. fumigatus isolates 10AF and AF13073. When VCZ and supernatants were combined at their IC50s, synergistic effects on A. fumigatus were found. Synergistic effects were no longer observed when P. aeruginosa supernatants were prepared in the presence of iron, or when P. aeruginosa mutants were lacking the ability to produce pyoverdine and pyochelin. Combination of pure P. aeruginosa products pyoverdine, pyochelin, and pyocyanin with VCZ showed synergistic anti-fungal effects. Combining VCZ with P. aeruginosa supernatants also improved its MIC and MFC against planktonic A. fumigatus. In summary, in the case of P. aeruginosa-A. fumigatus co-infections, it appeared that the P. aeruginosa co-infection facilitated therapy of the Aspergillus; lower concentrations of VCZ might be sufficient to control fungal growth.

PMID:33925818 | DOI:10.3390/pathogens10050519

J Pers Med. 2021 Apr 27;11(5):350. doi: 10.3390/jpm11050350.

ABSTRACT

Ivacaftor has been shown to restore the functionality of the S1251N (also known as c.3752G>A) mutated CFTR, which may cause alterations in both airway and gut physiology and micro-environment, resulting in a change of microbiota in these organs. The aim of the present study was to analyze the effects of ivacaftor on the microbial community composition of both airway and gut in subjects with CF carrying one S1251N mutation, using a 16S rRNA gene-based sequencing approach. In 16 subjects with CF, repetitive samples from airways and gut were collected just before, and 2 months after, and, for 8 patients, also 9 and 12 months after, start of ivacaftor. 16S rRNA based sequencing identified 344 operational taxonomical units (OTUs) in a total of 139 samples (35 nasopharyngeal, 39 oropharyngeal, 29 sputum, and 36 fecal samples). Ivacaftor significantly enhanced bacterial diversity and overall microbiota composition in the gut (p < 0.01). There were no significant changes in the overall microbial composition and alpha diversity in upper and lower airways of these patients after ivacaftor treatment. Treatment with ivacaftor induces changes in gut microbiota whereas airway microbiota do not change significantly over time.

PMID:33925519 | DOI:10.3390/jpm11050350

Toxins (Basel). 2021 Apr 28;13(5):317. doi: 10.3390/toxins13050317.

ABSTRACT

Methicillin-resistant Staphylococcus aureus (MRSA) can cause chronic lung infections in patients with Cystic Fibrosis (CF). One option for managing them is the use of linezolid. We hereby report the in-host emergence of linezolid resistance (LR) in MRSA in CF siblings via a population analysis. A collection of 171 MRSA strains from 68 samples were characterized by determining their linezolid Minimal Inhibitory Concentrations (MICs), analyzing the locus of staphylococcal protein A (spa) and whole genome sequencing. Courses of linezolid were retraced. Strains belonged to three spa types (t002, t045, t127) and two sequence types (ST1, ST5). Emergence of LR occurred under treatment, one year apart in both siblings, in the CC5-MRSA-I Geraldine clone harboring the toxic shock syndrome toxin-1-encoding gene. Resistance was related to a G2576T substitution present in a variable number of 23S rRNA gene copies. Susceptible and resistant strains were co-isolated within samples. Single Nucleotide Polymorphism-based analysis revealed complex colonizations by highly diversified, clonally related populations. LR remains rare in MRSA and there are very few longitudinal analyses documenting its emergence. Analyzing a large MRSA collection revealed new aspects of LR emergence: it emerges in specific subclonal lineages resulting from adaptive diversification of MRSA in the CF lung and this heterogeneity of intra-sample resistance may contribute to compromising antibiotic management.

PMID:33925199 | DOI:10.3390/toxins13050317

Int J Environ Res Public Health. 2021 Apr 28;18(9):4691. doi: 10.3390/ijerph18094691.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) is one of the most common inherited diseases. It is characterised by a severe decline in pulmonary function associated with metabolic perturbations and an increased production of inflammatory cytokines. The key role of physical activity (PA) in improving the health status of CF patients and reducing lung function decline has recently been demonstrated. This study evaluated interleukin-6 (IL-6) and tumour necrosis factor α (TNFα) expression in two subgroups of CF patients classified based on PA.

METHODS: We selected 85 CF patients; half of them regularly undertook supervised PA in the three years leading up to the study and half of them were not physically active. Patients were analysed for serum IL-6 and TNFα levels using enzyme-linked immunosorbent assays.

RESULTS: We found that the expression levels of IL-6 and TNFα differed in terms of their regulation by PA. In particular, TNFα levels negatively correlated with FEV1% decrease/year and FEV1% decrease (p = 0.023 and p = 0.02, respectively), and positively correlated with serum fasting glucose (p = 0.019) in PA CF patients. In contrast, in the NPA subgroup, TNFα levels were positively correlated with IL-6 (p = 0.001) and negatively correlated with adiponectin (p = 0.000). In addition, multiple logistic regression analysis confirmed that PA is an independent modulator of the inflammatory state.

CONCLUSIONS: PA modulates inflammatory processes in CF patients by regulating the secretion of pro-inflammatory cytokines and thus ameliorating lung function. Our data show that PA is a useful complementary strategy in the management of CF and that TNFα may be a marker of these effects of PA.

PMID:33924887 | DOI:10.3390/ijerph18094691

Int J Mol Sci. 2021 Apr 13;22(8):4003. doi: 10.3390/ijms22084003.

ABSTRACT

Bacteria form multicellular and resistant structures named biofilms. Biofilm formation starts with the attachment phase, and the molecular actors involved in this phase, except adhesins, are poorly characterized. There is growing evidence that phospholipids are more than simple structural bricks. They are involved in bacterial adaptive physiology, but little is known about their role in biofilm formation. Here, we report a mass spectrometry analysis of the phospholipid (PL) profile of several strains of Pseudomonas aeruginosa isolated from cystic fibrosis patients. The aim of our study was to evaluate a possible link between the PL profile of a strain and its attachment phenotype. Our results showed that PL profile is strongly strain-dependent. The PL profile of P. aeruginosa PAO1, a collection strain, was different from those of 10 clinical isolates characterized either by a very low or a very high attachment capacity. We observed also that the clinical strain's PL profiles varied even more importantly between isolates. By comparing groups of strains having similar attachment capacities, we identified one PL, PE 18:1-18:1, as a potential molecular actor involved in attachment, the first step in biofilm formation. This PL represents a possible target in the fight against biofilms.

PMID:33924531 | DOI:10.3390/ijms22084003

Genes (Basel). 2021 Apr 13;12(4):562. doi: 10.3390/genes12040562.

ABSTRACT

Our understanding of cystic fibrosis (CF) has grown exponentially since the discovery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in 1989. With evolving genetic and genomic tools, we have come to better understand the role of CFTR genotypes in the pathophysiology of the disease. This, in turn, has paved the way for the development of modulator therapies targeted at mutations in the CFTR, which are arguably one of the greatest advances in the treatment of CF. These modulator therapies, however, do not target all the mutations in CFTR that are seen in patients with CF and, furthermore, a variation in response is seen in patients with the same genotype who are taking modulator therapies. There is growing evidence to support the role of non-CFTR modifiers, both genetic and environmental, in determining the variation seen in CF morbidity and mortality and also in the response to existing therapies. This review focusses on key findings from studies using candidate gene and genome-wide approaches to identify CF modifier genes of lung disease in cystic fibrosis and considers the interaction between modifiers and the response to modulator therapies. As the use of modulator therapies expands and we gain data around outcomes, it will be of great interest to investigate this interaction further. Going forward, it will also be crucial to better understand the relative influence of genomic versus environmental factors. With this understanding, we can truly begin to deliver personalised care by better profiling the likely disease phenotype for each patient and their response to treatment.

PMID:33924524 | DOI:10.3390/genes12040562

Int J Mol Sci. 2021 Apr 20;22(8):4252. doi: 10.3390/ijms22084252.

ABSTRACT

Human small heat shock proteins are molecular chaperones that regulate fundamental cellular processes in normal and pathological cells. Here, we have reviewed the role played by HspB1, HspB4 and HspB5 in the context of Cystic Fibrosis (CF), a severe monogenic autosomal recessive disease linked to mutations in Cystic Fibrosis Transmembrane conductance Regulator protein (CFTR) some of which trigger its misfolding and rapid degradation, particularly the most frequent one, F508del-CFTR. While HspB1 and HspB4 favor the degradation of CFTR mutants, HspB5 and particularly one of its phosphorylated forms positively enhance the transport at the plasma membrane, stability and function of the CFTR mutant. Moreover, HspB5 molecules stimulate the cellular efficiency of currently used CF therapeutic molecules. Different strategies are suggested to modulate the level of expression or the activity of these small heat shock proteins in view of potential in vivo therapeutic approaches. We then conclude with other small heat shock proteins that should be tested or further studied to improve our knowledge of CFTR processing.

PMID:33923911 | DOI:10.3390/ijms22084252

Viruses. 2021 Apr 16;13(4):686. doi: 10.3390/v13040686.

ABSTRACT

Aspergillus and Pseudomonas compete in nature, and are the commonest bacterial and fungal pathogens in some clinical settings, such as the cystic fibrosis lung. Virus infections of fungi occur naturally. Effects on fungal physiology need delineation. A common reference Aspergillus fumigatus strain, long studied in two (of many) laboratories, was found infected with the AfuPmV-1 virus. One isolate was cured of virus, producing a virus-free strain. Virus from the infected strain was purified and used to re-infect three subcultures of the virus-free fungus, producing six fungal strains, otherwise isogenic. They were studied in intermicrobial competition with Pseudomonasaeruginosa. Pseudomonas culture filtrates inhibited forming or preformed Aspergillus biofilm from infected strains to a greater extent, also seen when Pseudomonas volatiles were assayed on Aspergillus. Purified iron-chelating Pseudomonas molecules, known inhibitors of Aspergillus biofilm, reproduced these differences. Iron, a stimulus of Aspergillus, enhanced the virus-free fungus, compared to infected. All infected fungal strains behaved similarly in assays. We show an important consequence of virus infection, a weakening in intermicrobial competition. Viral infection may affect the outcome of bacterial-fungal competition in nature and patients. We suggest that this occurs via alteration in fungal stress responses, the mechanism best delineated here is a result of virus-induced altered Aspergillus iron metabolism.

PMID:33923408 | DOI:10.3390/v13040686

Int J Mol Sci. 2021 Apr 24;22(9):4448. doi: 10.3390/ijms22094448.

ABSTRACT

The emergence of highly effective CFTR modulator therapy has led to significant improvements in health care for most patients with cystic fibrosis (CF). For some, however, these therapies remain inaccessible due to the rarity of their individual CFTR variants, or due to a lack of biologic activity of the available therapies for certain variants. One proposed method of addressing this gap is the use of primary human cell-based models, which allow preclinical therapeutic testing and physiologic assessment of relevant tissue at the individual level. Nasal cells represent one such tissue source and have emerged as a powerful model for individual disease study. The ex vivo culture of nasal cells has evolved over time, and modern nasal cell models are beginning to be utilized to predict patient outcomes. This review will discuss both historical and current state-of-the art use of nasal cells for study in CF, with a particular focus on the use of such models to inform personalized patient care.

PMID:33923202 | DOI:10.3390/ijms22094448

Cells. 2021 Apr 25;10(5):1014. doi: 10.3390/cells10051014.

ABSTRACT

Cystic fibrosis (CF) is caused by genetic mutations of the CF transmembrane conductance regulator (CFTR), leading to disrupted transport of Cl- and bicarbonate and CF lung disease featuring bacterial colonization and chronic infection in conducting airways. CF pigs engineered by mutating CFTR develop lung disease that mimics human CF, and are well-suited for investigating CF lung disease therapeutics. Clinical data suggest small airways play a key role in the early pathogenesis of CF lung disease, but few preclinical studies have focused on small airways. Efficient targeted delivery of CFTR cDNA to small airway epithelium may correct the CFTR defect and prevent lung infections. Adeno-associated virus 4 (AAV4) is a natural AAV serotype and a safe vector with lower immunogenicity than other gene therapy vectors such as adenovirus. Our analysis of AAV natural serotypes using cultured primary pig airway epithelia showed that AAV4 has high tropism for airway epithelia and higher transduction efficiency for small airways compared with large airways. AAV4 mediated the delivery of CFTR, and corrected Cl- transport in cultured primary small airway epithelia from CF pigs. Moreover, AAV4 was superior to all other natural AAV serotypes in transducing ITGα6β4+ pig distal lung progenitor cells. In addition, AAV4 encoding eGFP can infect pig distal lung epithelia in vivo. This study demonstrates AAV4 tropism in small airway progenitor cells, which it efficiently transduces. AAV4 offers a novel tool for mechanistical study of the role of small airway in CF lung pathogenesis in a preclinical large animal model.

PMID:33923029 | DOI:10.3390/cells10051014

Antibiotics (Basel). 2021 Apr 23;10(5):491. doi: 10.3390/antibiotics10050491.

ABSTRACT

Pseudomonas aeruginosa is one of the most critical bacterial pathogens associated with chronic infections in cystic fibrosis patients. Here we show the phenotypic and genotypic characterization of five consecutive multidrug-resistant isolates of P. aeruginosa collected during a month from a CF patient with end-stage lung disease and fatal outcome. The isolates exhibited distinct colony morphologies and pigmentation and differences in their capacity to produce biofilm and virulence potential evaluated in larvae of Galleria mellonella. Whole genome-sequencing showed that isolates belonged to a novel sequence type ST3449 and serotype O6. Analysis of their resistome demonstrated the presence of genes blaOXA-396, blaPAO, aph(3')-IIb, catB, crpP and fosA and new mutations in chromosomal genes conferring resistance to different antipseudomonal antibiotics. Genes exoS, exoT, exoY, toxA, lasI, rhlI and tse1 were among the 220 virulence genes detected. The different phenotypic and genotypic features found reveal the adaptation of clone ST3449 to the CF lung environment by a number of mutations affecting genes related with biofilm formation, quorum sensing and antimicrobial resistance. Most of these mutations are commonly found in CF isolates, which may give us important clues for future development of new drug targets to combat P. aeruginosa chronic infections.

PMID:33922748 | DOI:10.3390/antibiotics10050491

Antibiotics (Basel). 2021 Apr 23;10(5):486. doi: 10.3390/antibiotics10050486.

ABSTRACT

Cystic fibrosis (CF) is a genetic disease that causes absence or dysfunction of a protein named transmembrane conductance regulatory protein (CFTR) that works as an anion channel. As a result, the secretions of the organs where CFTR is expressed are very viscous, so their functionality is altered. The main cause of morbidity is due to the involvement of the respiratory system as a result of recurrent respiratory infections by different pathogens. In recent decades, survival has been increasing, rising by around age 50. This is due to the monitoring of patients in multidisciplinary units, early diagnosis with neonatal screening, and advances in treatments. In this chapter, we will approach the different therapies used in CF for the treatment of symptoms, obstruction, inflammation, and infection. Moreover, we will discuss specific and personalized treatments to correct the defective gene and repair the altered protein CFTR. The obstacle for personalized CF treatment is to predict the drug response of patients due to genetic complexity and heterogeneity of uncommon mutations.

PMID:33922413 | DOI:10.3390/antibiotics10050486

Biomedicines. 2021 Apr 22;9(5):458. doi: 10.3390/biomedicines9050458.

ABSTRACT

The search for biomarkers that can help to establish an early diagnosis and prognosis of interstitial lung disease (ILD) is of potential interest. VEGF polymorphisms have been implicated in the development of several lung disorders. Consequently, we assessed, for the first time, the role of VEGF polymorphisms in the susceptibility and severity of ILD. A total of 436 Caucasian ILD patients (244 with idiopathic interstitial pneumonias (IIPs) and 192 with non-IIP) and 536 ethnically-matched healthy controls were genotyped for VEGF rs833061, rs1570360, rs2010963, rs3025020, and rs3025039 polymorphisms by TaqMan assays. Pulmonary function tests were collected from all the patients. VEGF serum levels were determined by ELISA in a subgroup of patients. No VEGF genotype, allele, carrier, or haplotype differences were found between ILD patients and controls as well as between IIP and non-IIP patients. However, an association of rs1570360 with IIP in women and also with lung function in IIP patients was found. None of the VEGF polymorphisms were associated with VEGF levels. In conclusion, our results suggest that VEGF does not seem to play a relevant role in ILD, although rs1570360 may influence the severity of ILD in women and a worse outcome in IIP patients.

PMID:33922301 | DOI:10.3390/biomedicines9050458

Antibiotics (Basel). 2021 Apr 12;10(4):424. doi: 10.3390/antibiotics10040424.

ABSTRACT

Acute kidney injury is a reversible medical condition commonly caused by nephrotoxic agents. The infrequency that a nebulized medication elicits a renal insult presents a rare diagnostic challenge. Within this case, we report a 57-year-old cystic fibrosis patient with chronic kidney disease (CKD) Stage G3b (baseline 1.5-1.6 mg/dL) who developed an acute kidney injury (AKI) with a serum creatinine elevation to 4.08 mg/dL and associated worsening vestibular dysfunction related to twice-daily nebulized tobramycin inhalation solution (TIS). The patient was found to have a tobramycin serum level of 4.2 μg/mL 2.5 h after TIS dosing, with elevation remaining present at 1.1 μg/mL 24 h after discontinuation of therapy. Laboratory values at one month continued to show elevated creatinine levels at 2.1 mg/dL, suggesting progression of his baseline CKD. This case supports the benefit of obtaining tobramycin serum levels and vestibular/audiology function testing when evaluating patients on chronic nebulized TIS who present with acute or chronic renal dysfunction. From these serum levels, adjustments to daily dosing, regular monitoring of tobramycin serum levels, or discontinuation of treatment should be made to prevent permanent renal damage in patients with CKD. Calculated Naranjo ADR Probability Scale: 9; Definite.

PMID:33921466 | DOI:10.3390/antibiotics10040424

Int J Mol Sci. 2021 Apr 12;22(8):3954. doi: 10.3390/ijms22083954.

ABSTRACT

Dry eye disease is one of the most common diseases, with increasing prevalence in many countries, but treatment options are limited. Cystic fibrosis transmembrane conductance regulator (CFTR) is a major ion channel that facilitates fluid secretion in ocular surface epithelium and is a potential target of therapeutic agent for the treatment of dry eye disease. In this study, we performed a cell-based, high-throughput screening for the identification of novel natural products that activate CFTR and restore the aqueous deficiency in dry eye. Screening of 1000 natural products revealed isorhamnetin, a flavonol aglycone, as a novel CFTR activator. Electrophysiological studies showed that isorhamnetin significantly increased CFTR chloride current, both wild type and ∆F508-CFTR. Isorhamnetin did not alter intracellular cAMP levels and the activity of other ion channels, including ANO1, ENaC, and hERG. Notably, application of isorhamnetin on mouse ocular surface induced CFTR activation and increased tear volume. In addition, isorhamnetin significantly reduced ocular surface damage and expression of interleukin (IL)-1β, IL-8, and tumor necrosis factor (TNF)-α in an experimental mouse model of dry eye. These data suggest that isorhamnetin may be used to treat dry eye disease.

PMID:33921231 | DOI:10.3390/ijms22083954

J Pers Med. 2021 Apr 15;11(4):302. doi: 10.3390/jpm11040302.

ABSTRACT

Familial hypercholesterolaemia (FH) is a common inherited cause of premature cardiovascular disease, but the majority of patients remain undiagnosed. The aim of this systematic review was to assess the effectiveness of interventions to systematically identify FH in primary care. No randomised, controlled studies were identified; however, three non-randomised intervention studies were eligible for inclusion. All three studies systematically identified FH using reminders (on-screen prompts) in electronic health records. There was insufficient evidence that providing comments on laboratory test results increased the identification of FH using the Dutch Lipid Clinic Network (DLCN) criteria. Similarly, using prompts combined with postal invitation demonstrated no significant increase in definite FH identification using Simon-Broome (SB) criteria; however, the identification of possible FH increased by 25.4% (CI 17.75 to 33.97%). Using on-screen prompts alone demonstrated a small increase of 0.05% (95% CI 0.03 to 0.07%) in identifying definite FH using SB criteria; however, when the intervention was combined with an outreach FH nurse assessment, the result was no significant increase in FH identification using a combination of SB and DLCN criteria. None of the included studies reported adverse effects associated with the interventions. Currently, there is insufficient evidence to determine which is the most effective method of systematically identifying FH in non-specialist settings.

PMID:33920869 | DOI:10.3390/jpm11040302

J Pers Med. 2021 Apr 15;11(4):301. doi: 10.3390/jpm11040301.

ABSTRACT

The rare Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) mutations, c.1826A > G (H609R) and c.3067_3072delATAGTG (I1023_V1024del), are associated with severe lung disease. Despite the existence of four CFTR targeted therapies, none have been approved for individuals with these mutations because the associated molecular defects were not known. In this study we examined the consequences of these mutations on protein processing and channel function in HEK293 cells. We found that, similar to F508del, H609R and I1023_V1024del-CFTR exhibited reduced protein processing and altered channel function. Because the I1023_V1024del mutation can be linked with the mutation, I148T, we also examined the protein conferred by transfection of a plasmid bearing both mutations. Interestingly, together with I148T, there was no further reduction in channel function exhibited by I1023-V1024del. Both H609R and I1023_V1024del failed to exhibit significant correction of their functional expression with lumacaftor and ivacaftor. In contrast, the triple modulator combination found in TRIKAFTATM, i.e., tezacaftor, elexacaftor and ivacaftor rescued trafficking and function of both of these mutants. These in-vitro findings suggest that patients harbouring H609R or I1023_V1024del, alone or with I148T, may benefit clinically from treatment with TRIKAFTATM.

PMID:33920764 | DOI:10.3390/jpm11040301

Materials (Basel). 2021 Apr 17;14(8):2030. doi: 10.3390/ma14082030.

ABSTRACT

Implants made of ceramic and metallic elements, which are used in dentistry, may either promote or hinder the colonization and adhesion of bacteria to the surface of the biomaterial to varying degrees. The increased interest in the use of dental implants, especially in patients with chronic systemic diseases such as cystic fibrosis (CF), is caused by an increase in disease complications. In this study, we evaluated the differences in the in vitro biofilm formation on the surface of biomaterials commonly used in dentistry (Ti-6Al-4V, cobalt-chromium alloy (CoCr), and zirconia) by Staphylococcus aureus isolated from patients with CF. We demonstrated that S. aureus adherence and growth depends on the type of material used and its surface topography. Weaker bacterial biofilm formation was observed on zirconia surfaces compared to titanium and cobalt-chromium alloy surfaces. Moreover, scanning electron microscopy showed clear differences in bacterial aggregation, depending on the type of biomaterial used. Over the past several decades, S. aureus strains have developed several mechanisms of resistance, especially in patients on chronic antibiotic treatment such as CF. Therefore, the selection of an appropriate implant biomaterial with limited microorganism adhesion characteristics can affect the occurrence and progression of oral cavity infections, particularly in patients with chronic systemic diseases.

PMID:33920743 | DOI:10.3390/ma14082030

Int J Mol Sci. 2021 Apr 10;22(8):3928. doi: 10.3390/ijms22083928.

ABSTRACT

The aim of this study was the identification of specific proteomic profiles, related to a restored cystic fibrosis transmembrane conductance regulator (CFTR) activity in cystic fibrosis (CF) leukocytes before and after ex vivo treatment with the potentiator VX770. We used leukocytes, isolated from CF patients carrying residual function mutations and eligible for Ivacaftor therapy, and performed CFTR activity together with proteomic analyses through micro-LC-MS. Bioinformatic analyses of the results obtained revealed the downregulation of proteins belonging to the leukocyte transendothelial migration and regulation of actin cytoskeleton pathways when CFTR activity was rescued by VX770 treatment. In particular, we focused our attention on matrix metalloproteinase 9 (MMP9), because the high expression of this protease potentially contributes to parenchyma lung destruction and dysfunction in CF. Thus, the downregulation of MMP9 could represent one of the possible positive effects of VX770 in decreasing the disease progression, and a potential biomarker for the prediction of the efficacy of therapies targeting the defect of Cl- transport in CF.

PMID:33920274 | DOI:10.3390/ijms22083928

Pharmaceutics. 2021 Apr 18;13(4):577. doi: 10.3390/pharmaceutics13040577.

ABSTRACT

The eradication of Pseudomonas aeruginosa in cystic fibrosis patients has become continuously difficult due to its increased resistance to treatments. This study assessed the efficacy of free and liposomal gentamicin and erythromycin, combined with Phenylalanine arginine beta-naphthylamide (PABN), a broad-spectrum efflux pump inhibitor, against P. aeruginosa isolates. Liposomes were prepared and characterized for their sizes and encapsulation efficiencies. The antimicrobial activities of formulations were determined by the microbroth dilution method. Their activity on P. aeruginosa biofilms was assessed, and the effect of sub-inhibitory concentrations on bacterial virulence factors, quorum sensing (QS) signals and bacterial motility was also evaluated. The average diameters of liposomes were 562.67 ± 33.74 nm for gentamicin and 3086.35 ± 553.95 nm for erythromycin, with encapsulation efficiencies of 13.89 ± 1.54% and 51.58 ± 2.84%, respectively. Liposomes and PABN combinations potentiated antibiotics by reducing minimum inhibitory and bactericidal concentrations by 4-32 fold overall. The formulations significantly inhibited biofilm formation and differentially attenuated virulence factor production as well as motility. Unexpectedly, QS signal production was not affected by treatments. Taken together, the results indicate that PABN shows potential as an adjuvant of liposomal macrolides and aminoglycosides in the management of lung infections in cystic fibrosis patients.

PMID:33919624 | DOI:10.3390/pharmaceutics13040577