Pseudomonas aeruginosa Utilizes Host-Derived Itaconate to Redirect Its Metabolism to Promote Biofilm Formation

Riquelme, Sebastián A.; Liimatta, Kalle; Lung, Tania Wong Fok; Fields, Blanche L.; Ahn, Danielle; Chen, David; Lozano, Carmen; Sáenz, Yolanda; Uhlemann, Anne‐Catrin; Kahl, Barbara C.; Britto, Clemente J.; DiMango, Emily

doi:10.1016/j.cmet.2020.04.017

Cited by 134 publications

(143 citation statements)

References 55 publications

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“…P. Aeruginosa is one of the most common pathogens to cause recurrent pulmonary infection in CF patients and exploits the host to maintain infection by inducing production of the TCA cycle metabolite itaconate in AMs. Itaconate exerts antimicrobial properties via inhibition of bacterial isocitrate lyase in the glyoxylate shunt 142 and to evade this mechanism P. Aeruginosa has developed a way to use itaconate as an energy source 143 . Similarly succinate, which is secreted in high levels during CF and especially during bacterial infection 144 , can be utilised by P. Aeruginosa and S. Aureus as a substrate to generate oxidative stress.…”

Section: Introductionmentioning

confidence: 99%

Macrophage metabolic reprogramming during chronic lung disease

Ogger

Byrne

2021

Mucosal Immunology

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Section: Introductionmentioning

confidence: 99%

Macrophage metabolic reprogramming during chronic lung disease

Ogger

Byrne

2021

Mucosal Immunology

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Section: Discussionmentioning

confidence: 61%

“…Despite the antimicrobial properties and bacterial growth inhibition of IA [29], the normal growth of PA in the medium supplemented with IA reported here might be due to the presence of glucose in the PPGAS culture medium [30]. Within a short-term incubation, IA induces membrane stress, which PA can balance by stress-response gene up-regulation [31]. Despite the short in vivo half-life, Cipro-a potent antibiotic, which inhibits bacterial DNA topoisomerase and DNA-gyrase [38]-has been formulated as a dry-powder [18] or liposomal inhalation therapy [16] for the treatment of pulmonary infections [39].…”

Section: Discussionmentioning

confidence: 62%

“…Furthermore, IA biological importance has also been proved by its contribution in loss-of-function mutations in ACOD1-the enzyme that catalyzes IA synthesis-which are extremely rare in human [27]. In contrast, extracellular pathogens, like PA, are able to encode enzymes that degrade IA to overcome the host defenses [30,31]. Biomedical uses of IA are in discovery and development phases.…”

Section: Introductionmentioning

confidence: 99%

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Itaconic Acid Increases the Efficacy of Tobramycin against Pseudomonas aeruginosa Biofilms

Rossi

Loretz

et al. 2020

Pharmaceutics

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The search for novel therapeutics against pulmonary infections, in particular Pseudomonas aeruginosa (PA) biofilm infections, has been intense to deal with the emergent rise of antimicrobial resistance. Despite the numerous achievements in drug discovery and delivery strategies, only a limited number of therapeutics reach the clinic. To allow a timely preclinical development, a formulation should be highly effective, safe, and most importantly facile to produce. Thus, a simple combination of known actives that enhances the therapeutic efficacy would be a preferential choice compared to advanced drug delivery systems. In this study, we propose a novel combination of an anti-inflammatory agent—itaconic acid (itaconate, IA)—and an approved antibiotic—tobramycin (Tob) or ciprofloxacin (Cipro). The combination of Tob and IA at a molar ratio of 1:5 increased the biofilm eradicating efficacy in the strain PA14 wild type (wt) by ~4-fold compared to Tob alone. In contrast, such effect was not observed for the combination of IA with Cipro. Subsequent studies on the influence of IA on bacterial growth, pyocyanin production, and Tob biofilm penetration indicated that complexation with IA enhanced the transport of Tob through the biofilm. We recommend the simple and effective combination of Tob:IA for further testing in advanced preclinical models of PA biofilm infections.

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“…This excessive ROS production activates the anti-oxidant cell response, which, in part, is mediated by itaconate. This metabolite is the product of Irg1 (in humans Acod1 ), and its activity is linked to, for example, inhibition of SDH [ 56 – 59 ]. Thus, PTEN deregulation induces oxidative stress in mitochondria and, as a compensatory mechanism, itaconate synthesis, which inhibits SDH and enable succinate accumulation and its release [ 30 , 60 ].…”

Section: Main Textmentioning

confidence: 99%

Airway immunometabolites fuel Pseudomonas aeruginosa infection

Riquelme

Prince

2020

Respir Res

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Pulmonary infections are associated with a brisk inflammatory reaction to bacterial surface components. Lipopolysaccharides (LPS) trigger macrophage activation and release of mitochondrial metabolites that control the intensity of the immune response. Whereas succinate induces oxidative stress (ROS), HIF1α stabilization, glycolysis and IL-1β release, itaconate suppresses inflammation by inhibiting succinate oxidation, glycolytic flux and promoting anti-oxidant Nrf2-HO-1 functions. P. aeruginosa is a major pathogen associated with acute and chronic lung infection. Although both secreted toxins, LPS and proteases are key factors to establish acute P. aeruginosa pneumonia, lack of these components in chronic P. aeruginosa isolates suggest these organisms exploit other mechanisms to adapt and persist in the lung. Upon inhalation, P. aeruginosa strains trigger airway macrophage reprograming and bacterial variants obtained from acutely and chronically infected subjects exhibit metabolic adaptation consistent with succinate and itaconate assimilation; namely, high expression of extracellular polysaccharides (EPS), reduced lptD-LPS function, increased glyoxylate shunt (GS) activity and substantial biofilm production. In this review we discuss recent findings illustrating how P. aeruginosa induces and adapts to macrophage metabolites in the human lung, and that catabolism of succinate and itaconate contribute to their formidable abilities to tolerate oxidative stress, phagocytosis and immune clearance.

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Pseudomonas aeruginosa Utilizes Host-Derived Itaconate to Redirect Its Metabolism to Promote Biofilm Formation

Abstract: Highlights d P. aeruginosa-infected macrophages produce itaconate d Itaconate generates membrane stress in P. aeruginosa d Itaconate leads to decreased LPS, but increased EPS, to promote biofilm formation d The EPS-itaconate axis thwarts immune clearance enabling chronic infection

Cited by 134 publications

References 55 publications

Macrophage metabolic reprogramming during chronic lung disease

Macrophage metabolic reprogramming during chronic lung disease

Itaconic Acid Increases the Efficacy of Tobramycin against Pseudomonas aeruginosa Biofilms

Airway immunometabolites fuel Pseudomonas aeruginosa infection

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