Phenotypic characterization of an international Pseudomonas aeruginosa reference panel: strains of cystic fibrosis (CF) origin show less in vivo virulence than non-CF strains

Cullen, Louise; Weiser, Rebecca; Olszak, Tomasz; Maldonado, Rita F.; Moreira, Ana S.; Slachmuylders, Lisa; Brackman, Gilles; Paunova-Krasteva, Tsvetelina; Żarnowiec, Paulina; Czerwonka, Grzegorz; Reilly, James; Dřevı́nek, Pavel; Kaca, Wiesław; Melter, Oto; Soyza, Anthony De; Perry, Audrey; Winstanley, Craig; Stoitsova, Stoyanka; Lavigne, Rob; Mahenthiralingam, Eshwar; Sá‐Correia, Isabel; Coenye, Tom; Drulis-Kawa, Zuzanna; Augustyniak, Daria; Valvano, Miguel A.; McClean, Siobhán

doi:10.1099/mic.0.000155

Cited by 82 publications

(77 citation statements)

References 60 publications

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“…This variability in MICs could be considered somewhat unexpected for what is essentially a novel antibiotic compound being administered to a naive population. However, recent studies have reported significant phenotypic and genotypic diversity within clinical populations, suggesting that adaptation to environmental or host-related factors may be widespread (46)(47)(48). While the mechanism of action of statin antimicrobial and antivirulence activity remains to be elucidated, some reports suggest the involvement of isoprenoids and membrane integrity (49).…”

Section: Effects Of Statins On In Vitro Bacterial Growthmentioning

confidence: 99%

Is There Potential for Repurposing Statins as Novel Antimicrobials?

Hennessy

Adams

Reen

et al. 2016

Antimicrob Agents Chemother

109

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bStatins are members of a class of pharmaceutical widely used to reduce high levels of serum cholesterol. In addition, statins have so-called "pleiotropic effects," which include inflammation reduction, immunomodulation, and antimicrobial effects. An increasing number of studies are emerging which detail the attenuation of bacterial growth and in vitro and in vivo virulence by statin treatment. In this review, we describe the current information available concerning the effects of statins on bacterial infections and provide insight regarding the potential use of these compounds as antimicrobial therapeutic agents. O ne of the major undisputed clinical breakthroughs of the 20th century was the discovery of the statin family of drugs. These compounds are renowned for their ability to lower cholesterol levels and are used to treat approximately 40 million individuals with high cholesterol levels worldwide. Since the discovery of mevastatin as a metabolic product of Penicillium citrinum in 1976 (1, 2), a total of nine statins have been characterized, seven of which are approved by the FDA to treat patients with high cholesterol. Structurally, statins are characterized by the presence of a conserved lactone ring (3). This structure is present as a hydrolyzed (active) form in all statins except for mevastatin, lovastatin, and simvastatin; in those statins, the lactone ring is hydrolyzed in the liver (4). Statins can be divided into two broad classes (Fig. 1). Type 1 statins are lipophilic and possess a butyryl side chain-they are said to structurally resemble mevastatin (3). Lovastatin, pravastatin, and simvastatin are type 1 statins. Type 2 statins are classically lipophobic and are distinguished from type 1 by the replacement of the butyryl side chain with a fluorophenol group and typically possess larger side chains than type 1 statins (3). Atorvastatin, cerivastatin, fluvastatin, pitavastatin, and rosuvastatin are type 2 statins.Statins exert their cholesterol-lowering effect by binding to the active site of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (HMGR), a rate-limiting enzyme involved in cholesterol biosynthesis (3). HMGR is an integral part of the mevalonate pathway, which not only is essential for cholesterol biosynthesis but also contributes to the production of isoprenoids, lipid compounds that are essential for cell signaling and structure. As well as inhibition of cholesterol, statins have also been found to have a number of cholesterol-independent, socalled "pleiotropic" effects. Statins have been reported to confer anti-inflammatory, immunomodulatory, and anticancer effects on host cells, and these effects are well characterized (5-9). Furthermore, several studies have explored the pleiotropic effects of statins in combating multisystem microbial infections, such as sepsis and pneumonia, and a growing number of studies are demonstrating that statins can directly influence the growth and virulence of bacterial pathogens. With the global increase in antibiotic resistance to existing antib...

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Section: Effects Of Statins On In Vitro Bacterial Growthmentioning

confidence: 99%

Is There Potential for Repurposing Statins as Novel Antimicrobials?

Hennessy

Adams

Reen

et al. 2016

Antimicrob Agents Chemother

109

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“…The lytic activity of PA5oct was examined on two independent P. aeruginosa panels. First, on the COST international reference panel of 43 clinical P. aeruginosa (Cullen et al , 2015). On that collection, phage PA5oct infects 24% of the isolates, a rate that is more limited when compared to representatives of the Luz7virus LUZ7 (42%), Phikmvvirus group (LUZ19 44%), Pbunavirus group (LBL3 40%, KT28 28%, KTN6 42%) and Phikzvirus group (phiKZ 47%, KTN4 33%).…”

Section: Resultsmentioning

confidence: 99%

Pseudomonas aeruginosa PA5oct jumbo phage impacts planktonic and biofilm population and reduces its host virulence

Olszak

Danis-Wlodarczyk

Arabski

et al. 2018

Preprint

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SummaryIn this work we analyzed the impact of jumbo phage PA5oct on the planktonic, cell line adhered, and biofilm population of P. aeruginosa. PA5oct has a broad host-range, able to infect up to 40% of our clinical P. aeruginosa Cystic Fibrosis (CF) collection. In the airway surface liquid (ASL) model, the infection of PA5oct effectively reduced the bacterial population both adhered to epithelial cells, mucus entrapped, and dispersed. The explanation for its infectivity can also be linked to the sensitization of infected bacteria to the innate immune mechanisms and pro-inflammatory effect. Interferometry of a 72-hour old biofilm highlighted the contribution of PA5oct in biofilm matrix degradation. Interestingly, two virion-associated proteins, gp162 and gp205, have been found as putative enzymes that can degrade matrix exopolysaccharides. Two third of biofilm clones developed PA5oct phage-resistance and the cross-resistance to both LPS- and pili-dependent phages. Simultaneously, all clones resistant to phage PA5oct maintain the phage DNA within the population, strongly reducing bacterial virulence in vivo. These properties can be considered as key parameters for the application of this bacterial virus in phage therapy settings.Originality-Significance StatementThe emergence of phage-resistant mutants is a key aspect of lytic phages-bacteria interaction and the main driver for the co-evolution between both organisms. However, this fundamental property also has implications for bacterial eradication in phage therapy settings. Here, we analyze the impact of PA5oct jumbo phage treatment of planktonic/cell line associated and sessile P. aeruginosa population in a preclinical evaluation of this phage for therapeutic applications. Besides its broad-spectrum activity and efficient bacteria reduction in both airway surface liquid (ASL) model, and biofilm matrix degradation, PA5oct appears to persist in most of phage-resistant clones. Indeed, a high percentage of resistance (20/30 clones) to PA5oct is accompanied by the presence of phage DNA within bacterial culture. Moreover, the maintenance of this phage in the bacterial population is correlated to reduced P. aeruginosa virulence, coupled with a sensitization to innate immune mechanisms, and a significantly reduced growth rate. We observed rather unusual consequences of PA5oct infection causing an increased inflammatory response of monocytes to P. aeruginosa. This, phenomenon combined with the loss or modification of the phage receptor makes most of the phage-resistant clones significantly less pathogenic in in vivo model. During phage therapy treatment, phage-resistance is considered as an adverse effect, but our results indicate that it leads to diminished bacterial virulence and increased clearance of the infected host. These findings provide new insights into the general knowledge of giant phages biology and the impact of their application in phage therapy.

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“…We also observed an increase in CFTR mRNA levels in treated tissues. Loss of CFTR function leads to the development of chronic bacterial lung infections (26, 27). In CF pigs, loss of CFTR-mediated bicarbonate transport leads to acidic airways and impaired bacterial killing (16).…”

Section: Discussionmentioning

confidence: 99%

Lentiviral-mediated phenotypic correction of cystic fibrosis pigs

Cooney¹,

Alaiwa²,

Shah³

et al. 2016

JCI Insight

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Cystic Fibrosis (CF) is an autosomal recessive disease caused by mutations in CF transmembrane conductance regulator (CFTR), resulting in defective anion transport. Regardless of the disease-causing mutation, gene therapy is a strategy to restore anion transport to airway epithelia. Indeed, viral vector–delivered CFTR can complement the anion channel defect. In this proof-of-principle study, functional in vivo CFTR channel activity was restored in the airways of CF pigs using a feline immunodeficiency virus–based (FIV-based) lentiviral vector pseudotyped with the GP64 envelope. Three newborn CF pigs received aerosolized FIV-CFTR to the nose and lung. Two weeks after viral vector delivery, epithelial tissues were analyzed for functional correction. In freshly excised tracheal and bronchus tissues and cultured ethmoid sinus cells, we observed a significant increase in transepithelial cAMP-stimulated current, evidence of functional CFTR. In addition, we observed increases in tracheal airway surface liquid pH and bacterial killing in CFTR vector–treated animals. Together, these data provide the first evidence to our knowledge that lentiviral delivery of CFTR can partially correct the anion channel defect in a large-animal CF model and validate a translational strategy to treat or prevent CF lung disease.

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Phenotypic characterization of an international Pseudomonas aeruginosa reference panel: strains of cystic fibrosis (CF) origin show less in vivo virulence than non-CF strains

Cited by 82 publications

References 60 publications

Is There Potential for Repurposing Statins as Novel Antimicrobials?

Is There Potential for Repurposing Statins as Novel Antimicrobials?

Pseudomonas aeruginosa PA5oct jumbo phage impacts planktonic and biofilm population and reduces its host virulence

Lentiviral-mediated phenotypic correction of cystic fibrosis pigs

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