Production of highly stable spray dried phage formulations for treatment of Pseudomonas aeruginosa lung infection

Chang, Yoon Kyung; Wong, John; Mathai, Ash; Morales, Sandra; Kutter, Elizabeth; Britton, Warwick J.; Li, Jian; Chan, Hak Kim

doi:10.1016/j.ejpb.2017.09.002

Cited by 90 publications

(101 citation statements)

References 41 publications

(55 reference statements)

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“…Phage therapy is the application of bacteria-specific viruses to combat uncontrolled and undesired bacteria, such as those associated with infectious disease (200). Phage therapy for Pa infections has more than 50 years of history but there is a recent resurgence of interest in this approach (201)(202)(203). There are several potential advantages of phage therapy that make it an appealing alternative or adjunct to conventional antibiotics.…”

Section: The Relevance Of Pf Studies For Lytic Phage Therapymentioning

confidence: 99%

Pf Bacteriophage and Their Impact on Pseudomonas Virulence, Mammalian Immunity, and Chronic Infections

et al. 2020

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Pf bacteriophage are temperate phages that infect the bacterium Pseudomonas aeruginosa, a major cause of chronic lung infections in cystic fibrosis (CF) and other settings. Pf and other temperate phages have evolved complex, mutualistic relationships with their bacterial hosts that impact both bacterial phenotypes and chronic infection. We and others have reported that Pf phages are a virulence factor that promote the pathogenesis of P. aeruginosa infections in animal models and are associated with worse skin and lung infections in humans. Here we review the biology of Pf phage and what is known about its contributions to pathogenesis and clinical disease. First, we review the structure, genetics, and epidemiology of Pf phage. Next, we address the diverse and surprising ways that Pf phages contribute to P. aeruginosa phenotypes including effects on biofilm formation, antibiotic resistance, and motility. Then, we cover data indicating that Pf phages suppress mammalian immunity at sites of bacterial infection. Finally, we discuss recent literature implicating Pf in chronic P. aeruginosa infections in CF and other settings. Together, these reports suggest that Pf bacteriophage have direct effects on P. aeruginosa infections and that temperate phages are an exciting frontier in microbiology, immunology, and human health.

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Section: The Relevance Of Pf Studies For Lytic Phage Therapymentioning

confidence: 99%

Pf Bacteriophage and Their Impact on Pseudomonas Virulence, Mammalian Immunity, and Chronic Infections

et al. 2020

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“…Crystallization reduces the molecular interactions (hydrogen bonding) between the sugar and protein, thereby denaturing the protein during dehydration 13,14 . Crystalline mannitol thus compromised phage stability in an earlier study, 1 whereas amorphous sugars preserved phage activity when co‐spray dried 1,2,5 …”

Section: Introductionmentioning

confidence: 95%

“…Delivering them as aerosols can achieve direct targeting in the lungs. The feasibility of bioengineering phages into inhalable powders by spray drying has been demonstrated in vitro 1‐6 along with efficacy studies in vivo 7,8 . In the production process, it is essential to preserve phage bioactivity in the dry state by suitable excipients.…”

Section: Introductionmentioning

confidence: 99%

“…In the production process, it is essential to preserve phage bioactivity in the dry state by suitable excipients. Disaccharides such as trehalose, sucrose, and lactose are reported to provide protection to phages during drying and subsequent storage 1‐6 . This concept of sugar‐imparted phage protection was originated from protein stabilization mechanisms 9,10 .…”

Section: Introductionmentioning

confidence: 99%

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Inhalable bacteriophage powders: Glass transition temperature and bioactivity stabilization

Chang

Kwok

Khanal

et al. 2020

Bioengineering & Transla Med

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Recent heightened interest in inhaled bacteriophage (phage) therapy for combating antibacterial resistance in pulmonary infections has led to the development of phage powder formulations. Although phages have been successfully bioengineered into inhalable powders with preserved bioactivity, the stabilization mechanism is yet unknown. This paper reports the first study investigating the stabilization mechanism for phages in these powders. Proteins and other biologics are known to be preserved in dry state within a glassy sugar matrix at storage temperatures (T s ) at least~50 C below the glass transition temperature (T g ). This is because at (T g − T s ) >50 C, molecules are sufficiently immobilized with reduced reactivity. We hypothesized that this glass stabilization mechanism may also be applicable to phages comprising mostly of proteins. In this study, spray dried powders of Pseudomonas phage PEV20 containing lactose and leucine as excipients were stored at 5, 25 or 50 C and 15 or 33% relative humidity (RH), followed by assessment of bioactivity (PEV20 stability) and physical properties. PEV20 was stable with negligible titer loss after storage at 5 C/15% RH for 250 days, while storage at 33% RH caused increased titer losses of 1 log 10 and 3 log 10 at 5 and 25 C, respectively. The plasticizing effect of water at 33% RH lowered the T g by 30 C, thus narrowing the gap between T s and T g to 19-28 C, which was insufficient for glass stabilization. In contrast, the (T g − T s ) values were higher (range, 46-65 C) under the drier condition of 15% RH, resulting in the improved stability which corroborated with the vitrification hypothesis. Furthermore, phage remained stable (≤1 log 10 ) when the (T g − T s ) value lay between 26-48 C, but became inactivated as the value fell below 20 C. In conclusion, this study demonstrated that phage can be sufficiently stabilized in spray dried powders by keeping Abbreviations: DSC, differential scanning calorimetry; RH, relative humidity; TGA, thermal gravimetric analysis.; XRD, X-ray diffraction pattern.

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“…Liquid phage formulations have a short shelf life. Currently, scientists are trying to use phages in a much more stable form as dried powder specially for pulmonary infections having a longer shelf life with ease to store, transport, and administer . Transdermal delivery of phages provides another stable and effective route of administration .…”

Section: Why Phage Therapy?mentioning

confidence: 99%

The dawn of phage therapy

Rehman

Ali

Khan

et al. 2019

Reviews in Medical Virology

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Bacteriophages or phages, being the most abundant entities on earth, represent a potential solution to a diverse range of problems. Phages are successful antibacterial agents whose use in therapeutics was hindered by the discovery of antibiotics. Eventually, because of the development and spread of antibiotic resistance among most bacterial species, interest in phage as therapeutic entities has returned, because their noninfectious nature to humans should make them safe for human nanomedicine.This review highlights the most recent advances and progress in phage therapy and bacterial hosts against which phage research is currently being conducted with respect to food, human, and marine pathogens. Bacterial immunity against phages and tactics of phage revenge to defeat bacterial defense systems are also summarized.We have also discussed approved phage-based products (whole phage-based products and phage proteins) and shed light on their influence on the eukaryotic host with respect to host safety and induction of immune response against phage preparations.Moreover, creation of phages with desirable qualities and their uses in cancer treatment, vaccine production, and other therapies are also reviewed to bring together evidence from the scientific literature about the potentials and possible utility of phage and phage encoded proteins in the field of therapeutics and industrial biotechnology.

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Production of highly stable spray dried phage formulations for treatment of Pseudomonas aeruginosa lung infection

Cited by 90 publications

References 41 publications

Pf Bacteriophage and Their Impact on Pseudomonas Virulence, Mammalian Immunity, and Chronic Infections

Pf Bacteriophage and Their Impact on Pseudomonas Virulence, Mammalian Immunity, and Chronic Infections

Inhalable bacteriophage powders: Glass transition temperature and bioactivity stabilization

The dawn of phage therapy

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