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A compensatory RNase E variation increases Iron Piracy and Virulence in multidrug-resistant Pseudomonas aeruginosa during Macrophage infection.

ABSTRACT: During chronic cystic fibrosis (CF) infections, evolved Pseudomonas aeruginosa antibiotic resistance is linked to increased pulmonary exacerbations, decreased lung function, and hospitalizations. However, the virulence mechanisms underlying worse outcomes caused by antibiotic resistant infections are poorly understood. Here, we investigated evolved aztreonam resistant P. aeruginosa virulence mechanisms. Using a macrophage infection model combined with genomic and transcriptomic analyses, we show that a compensatory mutation in the rne gene, encoding RNase E, increased pyoverdine and pyochelin siderophore gene expression, causing macrophage ferroptosis and lysis. We show that iron-bound pyochelin was sufficient to cause macrophage ferroptosis and lysis, however, apo-pyochelin, iron-bound pyoverdine, or apo-pyoverdine were insufficient to kill macrophages. Macrophage killing could be eliminated by treatment with the iron mimetic gallium. RNase E variants were abundant in clinical isolates, and CF sputum gene expression data show that clinical isolates phenocopied RNase E variant functions during macrophage infection. Together these data show how P. aeruginosa RNase E variants can cause host damage via increased siderophore production and host cell ferroptosis but may also be targets for gallium precision therapy.

SUBMITTER: Vaillancourt M

PROVIDER: S-EPMC10115287 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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A compensatory RNase E variation increases Iron Piracy and Virulence in multidrug-resistant Pseudomonas aeruginosa during Macrophage infection.

Vaillancourt Mylene M Galdino Anna Clara Milesi ACM Limsuwannarot Sam P SP Celedonio Diana D Dimitrova Elizabeth E Broerman Matthew M Bresee Catherine C Doi Yohei Y Lee Janet S JS Parks William C WC Jorth Peter P

PLoS pathogens 20230407 4

During chronic cystic fibrosis (CF) infections, evolved Pseudomonas aeruginosa antibiotic resistance is linked to increased pulmonary exacerbations, decreased lung function, and hospitalizations. However, the virulence mechanisms underlying worse outcomes caused by antibiotic resistant infections are poorly understood. Here, we investigated evolved aztreonam resistant P. aeruginosa virulence mechanisms. Using a macrophage infection model combined with genomic and transcriptomic analyses, we show ...[more]

PMID: 37027441

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Project description:IntroductionPatients with nosocomial infections are at risk of multidrug-resistant (MDR) Pseudomonas aeruginosa since these bacteria slow down the entire treatment process, increasing the morbidity and mortality of patients staying in hospital. The purpose of the research was to assess the simultaneous presence of multidrug resistance and virulence factors among nosocomial strains of P. aeruginosa to evaluate significant association among them.MethodsOne hundred and eight clinical isolates of P. aeruginosa were found in a variety of samples taken from patients having nosocomial infection, including wound swabs, pus, sputum, tracheal aspirate, and urine. An antibiogram was performed to investigate the pathogen's antibiotic sensitivity pattern against 14 widely used antibiotics in Bangladesh. Virulence factors were evaluated, and the presence of ten β-lactamase and six virulence genes was analyzed by performing PCR. By using a binary logistic regression test with a 95% confidence interval, the relationship between MDR phenotypes and the virulence attributes was assessed.ResultsThe susceptibility rate among the isolates was 70-75% for aminoglycosides (amikacin, gentamicin, netilmicin), 15-20% for cephalosporins (ceftazidime, ceftriaxone), 30-35% for quinolones (ciprofloxacin, levofloxacin), 10-15% for tetracyclines (tigecycline, doxycycline), 15-20% for carbapenem (meropenem), 10-15% for sulfonamide (co-trimoxazole), 5-10% for amoxiclav, and 30-35% for piperacillin/tazobactam. A total of 74.1% of the strains carried metallo-β-lactamase (MBL) genes. Among the isolates, 89% showed hemolytic activity, 80-90% produced different pigments such as fluorescein and pyoverdine, 46% were strong biofilm producers, and all the isolates presented different types of motilities (swimming, swarming, and twitching). The virulence genes (lasB, exoS, toxA, aprA, algD, and plcH) were detected within a range of 60-80% of the isolates.DiscussionOnly the toxA gene and twitching motility showed a significant correlation (p-value = 0.001 and 0.028, respectively) with multidrug resistance in the clinical P. aeruginosa isolates which indicates that it can be used as a drug target to combat these organisms. The high prevalence of MDR strains and their association with virulence factors revealed the potential of the pathogen to cause an infection. The current study advocates for immediate epidemiological surveillance of MDR P. aeruginosa strains in Bangladesh to impede the rapid dissemination of this opportunistic pathogen.

Project description:BackgroundWe aimed to identify the main spreading clones, describe the resistance mechanisms associated with carbapenem- and/or multidrug-resistant P. aeruginosa and characterize patients at risk of acquiring these strains in Estonian hospitals.MethodsNinety-two non-duplicated carbapenem- and/or multidrug-resistant P. aeruginosa strains were collected between 27th March 2012 and 30th April 2013. Clinical data of the patients was obtained retrospectively from the medical charts. Clonal relationships of the strains were determined by whole genome sequencing and analyzed by multi-locus sequence typing. The presence of resistance genes and beta-lactamases and their origin was determined. Combined-disk method and PCR was used to evaluate carbapenemase and metallo-beta-lactamase production.ResultsForty-three strains were carbapenem-resistant, 11 were multidrug-resistant and 38 were both carbapenem- and multidrug-resistant. Most strains (54%) were isolated from respiratory secretions and caused an infection (74%). Over half of the patients (57%) were ≥ 65 years old and 85% had ≥1 co-morbidity; 96% had contacts with healthcare and/or had received antimicrobial treatment in the previous 90 days. Clinically relevant beta-lactamases (OXA-101, OXA-2 and GES-5) were found in 12% of strains, 27% of which were located in plasmids. No Ambler class B beta-lactamases were detected. Aminoglycoside modifying enzymes were found in 15% of the strains. OprD was defective in 13% of the strains (all with CR phenotype); carbapenem resistance triggering mutations (F170 L, W277X, S403P) were present in 29% of the strains. Ciprofloxacin resistance correlated well with mutations in topoisomerase genes gyrA (T83I, D87N) and parC (S87 L). Almost all strains (97%) with these mutations showed ciprofloxacin-resistant phenotype. Multi-locus sequence type analysis indicated high diversity at the strain level - 36 different sequence types being detected. Two sequence types (ST108 (n = 23) and ST260 (n = 18)) predominated. Whereas ST108 was associated with localized spread in one hospital and mostly carbapenem-resistant phenotype, ST260 strains occurred in all hospitals, mostly with multi-resistant phenotype and carried different resistance genotype/machinery.ConclusionsDiverse spread of local rather than international P. aeruginosa strains harboring multiple chromosomal mutations, but not plasmid-mediated Ambler class B beta-lactamases, were found in Estonian hospitals.Trial registrationThis trial was registered retrospectively in ClinicalTrials.gov ( NCT03343119 ).

Dataset Information

A compensatory RNase E variation increases Iron Piracy and Virulence in multidrug-resistant Pseudomonas aeruginosa during Macrophage infection.

Publications

A compensatory RNase E variation increases Iron Piracy and Virulence in multidrug-resistant Pseudomonas aeruginosa during Macrophage infection.

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