Development of inhalable hyaluronan/mannitol composite dry powders for flucytosine repositioning in local therapy of lung infections

Costabile, Gabriella; d’Angelo, Ivana; Bianca, Roberta d’Emmanuele di Villa; Mitidieri, Emma; Pompili, Barbara; Porto, Paola Del; Leoni, Livia; Visca, Paolo; Miro, Agnese; Quaglia, Fabiana; Imperi, Francesco; Sorrentino, Raffaella; Ungaro, Francesca

doi:10.1016/j.jconrel.2016.07.029

Cited by 26 publications

(18 citation statements)

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“…For example, it was recently discovered that pyoverdine, a siderophore produced by P. aeruginosa , is required for pathogenesis in Caenorhabditis elegans [ 3 , 4 ] and many mammalian infection models [ 5 , 6 , 7 , 8 ]. Small molecules that inhibit its biosynthesis have been shown to effectively limit P. aeruginosa pathogenesis, providing a promising approach to tackle antimicrobial resistance in this microorganism [ 7 , 9 , 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

Pyoverdine, a siderophore from Pseudomonas aeruginosa, translocates into C. elegans, removes iron, and activates a distinct host response

et al. 2018

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Pseudomonas aeruginosa, a re-emerging, opportunistic human pathogen, encodes a variety of virulence determinants. Pyoverdine, a siderophore produced by this bacterium, is essential for pathogenesis in mammalian infections. This observation is generally attributed to its roles in acquiring iron and/or regulating other virulence factors. Here we report that pyoverdine translocates into the host, where it binds and extracts iron. Pyoverdine-mediated iron extraction damages host mitochondria, disrupting their function and triggering mitochondrial turnover via autophagy. The host detects this damage via a conserved mitochondrial surveillance pathway mediated by the ESRE network. Our findings illuminate the pathogenic mechanisms of pyoverdine and highlight the importance of this bacterial product in host-pathogen interactions.

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Section: Introductionmentioning

confidence: 99%

Pyoverdine, a siderophore from Pseudomonas aeruginosa, translocates into C. elegans, removes iron, and activates a distinct host response

et al. 2018

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“…Fourth, the iron provided by pyoverdine is required for biofilm formation (Banin et al, 2005). Finally, and perhaps most importantly, fluoropyrimidines have been successfully used in several hosts to target pyoverdine, which has substantially reduced host mortality (Imperi et al, 2013; Costabile et al, 2016; Kirienko et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Novel Pyoverdine Inhibitors Mitigate Pseudomonas aeruginosa Pathogenesis

2019

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Pseudomonas aeruginosa is a clinically important pathogen that causes a variety of infections, including urinary, respiratory, and other soft-tissue infections, particularly in hospitalized patients with immune defects, cystic fibrosis, or significant burns. Antimicrobial resistance is a substantial problem in P. aeruginosa treatment due to the inherent insensitivity of the pathogen to a wide variety of antimicrobial drugs and its rapid acquisition of additional resistance mechanisms. One strategy to circumvent this problem is the use of anti-virulent compounds to disrupt pathogenesis without directly compromising bacterial growth. One of the principle regulatory mechanisms for P. aeruginosa’s virulence is the iron-scavenging siderophore pyoverdine, as it governs in-host acquisition of iron, promotes expression of multiple virulence factors, and is directly toxic. Some combination of these activities renders pyoverdine indispensable for pathogenesis in mammalian models. Here we report identification of a panel of novel small molecules that disrupt pyoverdine function. These molecules directly act on pyoverdine, rather than affecting its biosynthesis. The compounds reduce the pathogenic effect of pyoverdine and improve the survival of Caenorhabditis elegans when challenged with P. aeruginosa by disrupting only this single virulence factor. Finally, these compounds can synergize with conventional antimicrobials, forming a more effective treatment. These compounds may help to identify, or be modified to become, viable drug leads in their own right. Finally, they also serve as useful tool compounds to probe pyoverdine activity.

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“…Multiple transcriptome analyses indicate that pyoverdine may also be involved in other aspects of P. aeruginosa pathogenesis, including quorum sensing and responding to reactive oxygen species (ROS) (Palma et al, 2004 ; Dietrich et al, 2006 ). Furthermore, small molecule pyoverdine biosynthesis inhibitors, such as 5-fluorocytosine and 5-fluorouridine are sufficient to rescue mice and C. elegans (Imperi et al, 2013 ; Costabile et al, 2016 ; Kirienko et al, 2016 ). This demonstrates the utility of limiting pyoverdine production in P. aeruginosa infections.…”

Section: Introductionmentioning

confidence: 99%

High-Throughput Genetic Screen Reveals that Early Attachment and Biofilm Formation Are Necessary for Full Pyoverdine Production by Pseudomonas aeruginosa

Kang

Kirienko

2017

Front. Microbiol.

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Pseudomonas aeruginosa is a re-emerging, multidrug-resistant, opportunistic pathogen that threatens the lives of immunocompromised patients, patients with cystic fibrosis, and those in critical care units. One of the most important virulence factors in this pathogen is the siderophore pyoverdine. Pyoverdine serves several critical roles during infection. Due to its extremely high affinity for ferric iron, pyoverdine gives the pathogen a significant advantage over the host in their competition for iron. In addition, pyoverdine can regulate the production of multiple bacterial virulence factors and perturb host mitochondrial homeostasis. Inhibition of pyoverdine biosynthesis decreases P. aeruginosa pathogenicity in multiple host models. To better understand the regulation of pyoverdine production, we developed a high-throughput genetic screen that uses the innate fluorescence of pyoverdine to identify genes necessary for its biosynthesis. A substantial number of hits showing severe impairment of pyoverdine production were in genes responsible for early attachment and biofilm formation. In addition to genetic disruption of biofilm, both physical and chemical perturbations also attenuated pyoverdine production. This regulatory relationship between pyoverdine and biofilm is particularly significant in the context of P. aeruginosa multidrug resistance, where the formation of biofilm is a key mechanism preventing access to antimicrobials and the immune system. Furthermore, we demonstrate that the biofilm inhibitor 2-amino-5,6-dimethylbenzimidazole effectively attenuates pyoverdine production and rescues Caenorhabditis elegans from P. aeruginosa-mediated pathogenesis. Our findings suggest that targeting biofilm formation in P. aeruginosa infections may have multiple therapeutic benefits and that employing an unbiased, systems biology-based approach may be useful for understanding the regulation of specific virulence factors and identifying novel anti-virulence therapeutics or new applications for existing therapies for P. aeruginosa infections.

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Development of inhalable hyaluronan/mannitol composite dry powders for flucytosine repositioning in local therapy of lung infections

Cited by 26 publications

References 50 publications

Pyoverdine, a siderophore from Pseudomonas aeruginosa, translocates into C. elegans, removes iron, and activates a distinct host response

Pyoverdine, a siderophore from Pseudomonas aeruginosa, translocates into C. elegans, removes iron, and activates a distinct host response

Novel Pyoverdine Inhibitors Mitigate Pseudomonas aeruginosa Pathogenesis

High-Throughput Genetic Screen Reveals that Early Attachment and Biofilm Formation Are Necessary for Full Pyoverdine Production by Pseudomonas aeruginosa

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