Dataset Information

Antibacterial and Antibiofilm Effects of Lactobacilli Strains against Clinical Isolates of Pseudomonas aeruginosa under Conditions Relevant to Cystic Fibrosis.

ABSTRACT: Therapy of lung infections sustained by Pseudomonas aeruginosa in cystic fibrosis (CF) patients is challenging due to the presence of a sticky mucus in the airways and the ability of the bacterium to form biofilm, which exhibits increased antibiotic tolerance. A lung-directed bacteriotherapy through the airway administration of probiotics could represent an alternative approach to probiotic diet supplementation to improve the benefits and clinical outcomes of this kind of intervention in CF patients. This study aims to evaluate the ability of probiotic strains to grow in artificial sputum medium (ASM), mimicking the CF lung microenvironment, and to affect the planktonic and biofilm growth of CF clinical strains of P. aeruginosa in the same conditions. The results demonstrate that Lacticaseibacillus rhamnosus and Lactiplantibacillus plantarum (LP) can grow in ASM. LP inhibited the planktonic growth of P. aeruginosa, while both lactobacilli reduced the pre-formed biofilm of P. aeruginosa. Interestingly, LP was demonstrated to reduce the amount of polysaccharides in the extracellular matrix of P. aeruginosa biofilms and to potentiate the antibiofilm effects of tobramycin. Overall, the results indicated that LP is a promising candidate as an adjuvant in the antimicrobial therapy of P. aeruginosa infections in CF patients.

SUBMITTER: Batoni G

PROVIDER: S-EPMC10376640 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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Antibacterial and Antibiofilm Effects of Lactobacilli Strains against Clinical Isolates of <i>Pseudomonas aeruginosa</i> under Conditions Relevant to Cystic Fibrosis.

Batoni Giovanna G Catelli Elisa E Kaya Esingül E Pompilio Arianna A Bianchi Marta M Ghelardi Emilia E Di Bonaventura Giovanni G Esin Semih S Maisetta Giuseppantonio G

Antibiotics (Basel, Switzerland) 20230707 7

Therapy of lung infections sustained by <i>Pseudomonas aeruginosa</i> in cystic fibrosis (CF) patients is challenging due to the presence of a sticky mucus in the airways and the ability of the bacterium to form biofilm, which exhibits increased antibiotic tolerance. A lung-directed bacteriotherapy through the airway administration of probiotics could represent an alternative approach to probiotic diet supplementation to improve the benefits and clinical outcomes of this kind of intervention in ...[more]

PMID: 37508254

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Project description:Pseudomonas aeruginosa is the most common pathogen infecting cystic fibrosis (CF) lungs, causing acute and chronic infections. Intrinsic and acquired antibiotic resistance allow P. aeruginosa to colonize and persist despite antibiotic treatment, making new therapeutic approaches necessary. Combining high-throughput screening and drug repurposing is an effective way to develop new therapeutic uses for drugs. This study screened a drug library of 3,386 drugs, mostly FDA approved, to identify antimicrobials against P. aeruginosa under physicochemical conditions relevant to CF-infected lungs. Based on the antibacterial activity, assessed spectrophotometrically against the prototype RP73 strain and 10 other CF virulent strains, and the toxic potential evaluated toward CF IB3-1 bronchial epithelial cells, five potential hits were selected for further analysis: the anti-inflammatory and antioxidant ebselen, the anticancer drugs tirapazamine, carmofur, and 5-fluorouracil, and the antifungal tavaborole. A time-kill assay showed that ebselen has the potential to cause rapid and dose-dependent bactericidal activity. The antibiofilm activity was evaluated by viable cell count and crystal violet assays, revealing carmofur and 5-fluorouracil as the most active drugs in preventing biofilm formation regardless of the concentration. In contrast, tirapazamine and tavaborole were the only drugs actively dispersing preformed biofilms. Tavaborole was the most active drug against CF pathogens other than P. aeruginosa, especially against Burkholderia cepacia and Acinetobacter baumannii, while carmofur, ebselen, and tirapazamine were particularly active against Staphylococcus aureus and B. cepacia. Electron microscopy and propidium iodide uptake assay revealed that ebselen, carmofur, and tirapazamine significantly damage cell membranes, with leakage and cytoplasm loss, by increasing membrane permeability. IMPORTANCE Antibiotic resistance makes it urgent to design new strategies for treating pulmonary infections in CF patients. The repurposing approach accelerates drug discovery and development, as the drugs' general pharmacological, pharmacokinetic, and toxicological properties are already well known. In the present study, for the first time, a high-throughput compound library screening was performed under experimental conditions relevant to CF-infected lungs. Among 3,386 drugs screened, the clinically used drugs from outside infection treatment ebselen, tirapazamine, carmofur, 5-fluorouracil, and tavaborole showed, although to different extents, anti-P. aeruginosa activity against planktonic and biofilm cells and broad-spectrum activity against other CF pathogens at concentrations not toxic to bronchial epithelial cells. The mode-of-action studies revealed ebselen, carmofur, and tirapazamine targeted the cell membrane, increasing its permeability with subsequent cell lysis. These drugs are strong candidates for repurposing for treating CF lung P. aeruginosa infections.

Project description:Clinical isolates of Pseudomonas aeruginosa from patients with cystic fibrosis (CF) are known to differ from those associated with non-CF hosts by colony morphology, drug susceptibility patterns, and genomic hypermutability. Pseudomonas aeruginosa isolates from CF patients have long been recognized for their overall reduced rate of antimicrobial susceptibility, but their intraclonal MIC heterogeneity has long been overlooked. Using two distinct cohorts of clinical strains (n = 224 from 56 CF patients, n = 130 from 68 non-CF patients) isolated in 2013, we demonstrated profound Etest MIC heterogeneity in CF P. aeruginosa isolates in comparison to non-CF P. aeruginosa isolates. On the basis of whole-genome sequencing of 19 CF P. aeruginosa isolates from 9 patients with heterogeneous MICs, the core genome phylogenetic tree confirmed the within-patient CF P. aeruginosa clonal lineage along with considerable coding sequence variability. No extrachromosomal DNA elements or previously characterized antibiotic resistance mutations could account for the wide divergence in antimicrobial MICs between P. aeruginosa coisolates, though many heterogeneous mutations in efflux and porin genes and their regulators were present. A unique OprD sequence was conserved among the majority of isolates of CF P. aeruginosa analyzed, suggesting a pseudomonal response to selective pressure that is common to the isolates. Genomic sequence data also suggested that CF pseudomonal hypermutability was not entirely due to mutations in mutL, mutS, and uvr. We conclude that the net effect of hundreds of adaptive mutations, both shared between clonally related isolate pairs and unshared, accounts for their highly heterogeneous MIC variances. We hypothesize that this heterogeneity is indicative of the pseudomonal syntrophic-like lifestyle under conditions of being "locked" inside a host focal airway environment for prolonged periods. IMPORTANCE Patients with cystic fibrosis endure "chronic focal infections" with a variety of microorganisms. One microorganism, Pseudomonas aeruginosa, adapts to the host and develops resistance to a wide range of antimicrobials. Interestingly, as the infection progresses, multiple isogenic strains of P. aeruginosa emerge and coexist within the airways of these patients. Despite a common parental origin, the multiple strains of P. aeruginosa develop vastly different susceptibility patterns to actively used antimicrobial agents-a phenomenon we define as "heterogeneous MICs." By sequencing pairs of P. aeruginosa isolates displaying heterogeneous MICs, we observed widespread isogenic gene lesions in drug transporters, DNA mismatch repair machinery, and many other structural or cellular functions. Coupled with the heterogeneous MICs, these genetic lesions demonstrated a symbiotic response to host selection and suggested evolution of a multicellular syntrophic bacterial lifestyle. Current laboratory standard interpretive criteria do not address the emergence of heterogeneous growth and susceptibilities in vitro with treatment implications.

Dataset Information

Antibacterial and Antibiofilm Effects of Lactobacilli Strains against Clinical Isolates of Pseudomonas aeruginosa under Conditions Relevant to Cystic Fibrosis.

Publications

Antibacterial and Antibiofilm Effects of Lactobacilli Strains against Clinical Isolates of <i>Pseudomonas aeruginosa</i> under Conditions Relevant to Cystic Fibrosis.

Similar Datasets

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