Novel Therapeutic Strategies Applied to Pseudomonas aeruginosa Infections in Cystic Fibrosis

Chirgwin, Michael E.; Dedloff, Margaret R.; Holban, Alina Maria; Gestal, Mónica Cartelle

doi:10.3390/ma12244093

Cited by 15 publications

(7 citation statements)

References 53 publications

(58 reference statements)

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“…A major disadvantage is the fast clearance of the antibiotic from the lungs, allowing bacteria regrowth. However, liposomes may provide a sustainable and continuous delivery [ 57 ], as is the case of the liposomal amikacin, an inhalation therapy that reduces P. aeruginosa load in cystic fibrosis patients [ 58 ]. The pharmaceutical behaviour of encapsulated lysins in terms of pharmacokinetics, pharmacodynamics, and toxicity is to be characterized.…”

Section: Discussionmentioning

confidence: 99%

Liposomal Delivery of Newly Identified Prophage Lysins in a Pseudomonas aeruginosa Model

Morais

Tanoeiro

Marques

et al. 2022

IJMS

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Pseudomonas aeruginosa is a Gram-negative opportunistic bacterium that presents resistance to several antibiotics, thus, representing a major threat to human and animal health. Phage-derived products, namely lysins, or peptidoglycan-hydrolyzing enzymes, can be an effective weapon against antibiotic-resistant bacteria. Whereas in Gram-positive bacteria, lysis from without is facilitated by the exposed peptidoglycan layer, this is not possible in the outer membrane-protected peptidoglycan of Gram-negative bacteria. Here, we suggest the encapsulation of lysins in liposomes as a delivery system against Gram-negative bacteria, using the model of P. aeruginosa. Bioinformatic analysis allowed for the identification of 38 distinct complete prophages within 66 P. aeruginosa genomes (16 of which newly sequenced) and led to the identification of 19 lysins of diverse sequence and function, 5 of which proceeded to wet lab analysis. The four purifiable lysins showed hydrolytic activity against Gram-positive bacterial lawns and, on zymogram assays, constituted of autoclaved P. aeruginosa cells. Additionally, lysins Pa7 and Pa119 combined with an outer membrane permeabilizer showed activity against P. aeruginosa cells. These two lysins were successfully encapsulated in DPPC:DOPE:CHEMS (molar ratio 4:4:2) liposomes with an average encapsulation efficiency of 33.33% and 32.30%, respectively. The application of the encapsulated lysins to the model P. aeruginosa led to a reduction in cell viability and resulted in cell lysis as observed in MTT cell viability assays and electron microscopy. In sum, we report here that prophages may be important sources of new enzybiotics, with prophage lysins showing high diversity and activity. In addition, these enzybiotics following their incorporation in liposomes were able to potentiate their antibacterial effect against the Gram-negative bacteria P. aeruginosa, used as the model.

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Section: Discussionmentioning

confidence: 99%

Liposomal Delivery of Newly Identified Prophage Lysins in a Pseudomonas aeruginosa Model

Morais

Tanoeiro

Marques

et al. 2022

IJMS

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“…Liposomes are cell-like vesicles formed by an agglomerate of phospholipids. Phospholipids are amphipathic due to a hydrophobic "tail" and a hydrophilic "head" (Figure 7) [19][20][21]. Because of this, they can spontaneously form liposomes when placed into polar, typically aqueous, media.…”

Section: Liposomesmentioning

confidence: 99%

The Case against Antibiotics and for Anti-Virulence Therapeutics

2021

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Although antibiotics have been indispensable in the advancement of modern medicine, there are downsides to their use. Growing resistance to broad-spectrum antibiotics is leading to an epidemic of infections untreatable by first-line therapies. Resistance is exacerbated by antibiotics used as growth factors in livestock, over-prescribing by doctors, and poor treatment adherence by patients. This generates populations of resistant bacteria that can then spread resistance genes horizontally to other bacterial species, including commensals. Furthermore, even when antibiotics are used appropriately, they harm commensal bacteria leading to increased secondary infection risk. Effective antibiotic treatment can induce bacterial survival tactics, such as toxin release and increasing resistance gene transfer. These problems highlight the need for new approaches to treating bacterial infection. Current solutions include combination therapies, narrow-spectrum therapeutics, and antibiotic stewardship programs. These mediate the issues but do not address their root cause. One emerging solution to these problems is anti-virulence treatment: preventing bacterial pathogenesis instead of using bactericidal agents. In this review, we discuss select examples of potential anti-virulence targets and strategies that could be developed into bacterial infection treatments: the bacterial type III secretion system, quorum sensing, and liposomes.

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“…In order to limit toxicity and reduce side effects while directly targeting the lungs, many studies took an interest in using aerosols as a method of administration. In this frame of mind, Levofloxacin was developed for CF patients to target P. aeruginosa infections (Chirgwin et al, 2019;Epps et al, 2019). This drug, derived from the fluoroquinolone family, inhibits topoisomerases, which is essential for the synthesis of bacterial DNA.…”

Section: New Development In Antibiotic Approachesmentioning

confidence: 99%

Novel Anti-Inflammatory Approaches for Cystic Fibrosis Lung Disease: Identification of Molecular Targets and Design of Innovative Therapies

Mitri

Bardin

et al. 2020

Front. Pharmacol.

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Cystic fibrosis (CF) is the most common genetic disorder among Caucasians, estimated to affect more than 70,000 people in the world. Severe and persistent bronchial inflammation and chronic bacterial infection, along with airway mucus obstruction, are hallmarks of CF lung disease and participate in its progression. Anti-inflammatory therapies are, therefore, of particular interest for CF lung disease. Furthermore, a better understanding of the molecular mechanisms involved in airway infection and inflammation in CF has led to the development of new therapeutic approaches that are currently under evaluation by clinical trials. These new strategies dedicated to CF inflammation are designed to treat different dysregulated aspects such as oxidative stress, cytokine secretion, and the targeting of dysregulated pathways. In this review, we summarize the current understanding of the cellular and molecular mechanisms that contribute to abnormal lung inflammation in CF, as well as the new anti-inflammatory strategies proposed to CF patients by exploring novel molecular targets and novel drug approaches.

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Novel Therapeutic Strategies Applied to Pseudomonas aeruginosa Infections in Cystic Fibrosis

Cited by 15 publications

References 53 publications

Liposomal Delivery of Newly Identified Prophage Lysins in a Pseudomonas aeruginosa Model

Liposomal Delivery of Newly Identified Prophage Lysins in a Pseudomonas aeruginosa Model

The Case against Antibiotics and for Anti-Virulence Therapeutics

Novel Anti-Inflammatory Approaches for Cystic Fibrosis Lung Disease: Identification of Molecular Targets and Design of Innovative Therapies

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