Wound healing potential of topical bacteriophage therapy on diabetic cutaneous wounds

Mendes, João João; Leandro, Clara; Côrte‐Real, Sofia; Barbosa, Raquel; Cavaco‐Silva, Patrícia; Melo‐Cristino, José; Górski, Andrzej; Garcia, Miguel

doi:10.1111/wrr.12056

Cited by 100 publications

(57 citation statements)

References 34 publications

(73 reference statements)

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“…The safety and efficacy of phage products for removal of this bacterium in a sinusitis sheep model have also been proven (16). Other applications of phages against S. aureus encompass improvements in wound healing developed on diabetic patients (17,18) and the treatment of chronic wounds (19). Previous results also showed the ability of phages to remove biofilms formed by staphylococcal species (20)(21)(22).…”

mentioning

confidence: 71%

Two Phages, phiIPLA-RODI and phiIPLA-C1C, Lyse Mono- and Dual-Species Staphylococcal Biofilms

Gutiérrez

Vandenheuvel

Martínez

et al. 2015

Appl Environ Microbiol

131

133

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Phage therapy is a promising option for fighting against staphylococcal infections. Two lytic phages, vB_SauM_phiIPLA-RODI (phiIPLA-RODI) and vB_SepM_phiIPLA-C1C (phiIPLA-C1C), belonging to the Myoviridae family and exhibiting wide host ranges, were characterized in this study. The complete genome sequences comprised 142,348 bp and 140,961 bp and contained 213 and 203 open reading frames, respectively. The gene organization was typical of Spounavirinae members, with long direct terminal repeats (LTRs), genes grouped into modules not clearly separated from each other, and several group I introns. In addition, four genes encoding tRNAs were identified in phiIPLA-RODI. Comparative DNA sequence analysis showed high similarities with two phages, GH15 and 676Z, belonging to the Twort-like virus genus (nucleotide identities of >84%); for phiIPLA-C1C, a high similarity with phage phiIBB-SEP1 was observed (identity of 80%). Challenge assays of phages phiIPLA-RODI and phiIPLA-C1C against planktonic staphylococcal cells confirmed their lytic ability, as they were able to remove 5 log units in 8 h. Exposure of biofilms to phages phiIPLA-RODI and phiIPLA-C1C reduced the amount of adhered bacteria to about 2 log units in both monospecies and dual-species biofilms, but phiIPLA-RODI turned out to be as effective as the mixture of both phages. Moreover, the frequencies of bacteriophage-insensitive mutants (BIMs) of Staphylococcus aureus and S. epidermidis with resistance to phiIPLA-RODI and phiIPLA-C1C were low, at 4.05 ؋ 10 ؊7 ؎ 2.34 ؋ 10 ؊9 and 1.1 ؋ 10 ؊7 ؎ 2.08 ؋ 10 ؊9 , respectively. Overall, a generally reduced fitness in the absence of phages was observed for BIMs, which showed a restored phage-sensitive phenotype in a few generations. These results confirm that lytic bacteriophages can be efficient biofilm-disrupting agents, supporting their potential as antimicrobials against staphylococcal infections.T wo staphylococcal species, Staphylococcus aureus and Staphylococcus epidermidis, are the main causes of nosocomial infections due to their ability to adhere to, colonize, and develop biofilms in medical devices and human organs (1). Staphylococcal biofilms are complex structures in which bacterial cells are surrounded by an extracellular material (polysaccharides, teichoic acids, proteins, and extracellular DNA) which confers protection against antibacterial drugs and the host immune system. In addition, growth of bacteria in a biofilm facilitates the development of antibiotic-resistant organisms (2). S. epidermidis is one of the most abundant species in the human skin microbiota, from which it easily reaches catheters, heart valves, and contact lenses. Despite being regarded as an innocuous bacterium, it is now accepted as an opportunistic pathogen and one of the most common causes of bacteremia in immunocompromised patients (3), preterm infants (4), and biofilm-related infections (5). In addition, resistance to methicillin due to the presence of the mecA gene is widely spread in hospital isolates (6). Similarly, virule...

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mentioning

confidence: 71%

Two Phages, phiIPLA-RODI and phiIPLA-C1C, Lyse Mono- and Dual-Species Staphylococcal Biofilms

Gutiérrez

Vandenheuvel

Martínez

et al. 2015

Appl Environ Microbiol

131

133

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“…Although the use of icosahedral viruses remains highly promising, attention has more recently shifted towards the use of bacteriophages for the detection and treatment of bacterial infections (Carson et al, 2010;Chibeu et al, 2012;Hodgson, 2013;Mendes et al, 2013;Seth et al, 2013;Takemura-Uchiyama et al, 2013;Vandenheuvel et al, 2013;Yilmaz et al, 2013). Bacteriophages have been used in the past in Eastern Europe and the former Soviet Union to treat bacterial infections; however, it is only over the past two decades, with the rising problem of antibiotic-resistant infections, that their potential use has re-emerged worldwide (Kaur et al, 2012).…”

Section: Bacterial Infectionsmentioning

confidence: 99%

Using viruses as nanomedicines

Kan-Davelaar

Hest

Cornelissen

et al. 2014

British J Pharmacology

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The field of nanomedicine involves the design and fabrication of novel nanocarriers for the intracellular delivery of therapeutic cargo or for use in molecular diagnostics. Although traditionally recognized for their ability to invade and infect host cells, viruses and bacteriophages have been engineered over the past decade as highly promising molecular platforms for the targeted delivery and treatment of many human diseases. Inherently biodegradable, the outer capsids of viruses are composed entirely of protein building blocks, which can be genetically or chemically engineered with molecular imaging reagents, targeting ligands and therapeutic molecules. While there are several examples of viruses as in vitro molecular cargo carriers, their potential for applications in nanomedicine has only recently emerged. Here we highlight recent developments towards the design and engineering of viruses for the treatment of cancer, bacterial infections and immune system-related diseases. LINKED ARTICLESThis article is part of a themed section on Nanomedicine. To view the other articles in this section visit http://dx

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“…1–3 Ulcer wounds with impaired healing and repeated infection lead to the risk of lower limb amputation. According to the American Diabetes Association, the incidence of foot ulceration in diabetic patients may reach 40%, making it a large healthcare burden.…”

mentioning

confidence: 99%

Protein Tyrosine Phosphatase 1B Impairs Diabetic Wound Healing Through Vascular Endothelial Growth Factor Receptor 2 Dephosphorylation

Zhang

Liu

et al. 2015

ATVB

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Objective Impaired wound healing is a major complication of diabetes mellitus. The mechanisms that govern wound healing, however, are complex and incompletely understood. In the present study, we determined the inhibitory role of protein tyrosine phosphatase 1B (PTP1B) in the process of diabetic wound healing. Approach and Results First, by comparing the wound healing process in PTP1B knockout (PTP1B−/−) mice, ob/ob mice and their wild-type littermates in the presence or absence of streptozotocin treatment, we showed that the inhibition of mouse wound healing in streptozotocin-induced diabetic conditions is because of the upregulation and activation of PTP1B. Second, the impaired wound healing in ob/ob mice and streptozotocin-treated wild-type mice was rescued by a PTP1B inhibitor. Third, PTP1B, which is upregulated under hyperglycemic condition, inhibited the tube formation, proliferation, and migration of human microvascular endothelial cells induced by vascular endothelial growth factor, whereas this inhibition was largely abolished by the PTP1B inhibitor. Finally, mechanism study further indicated that PTP1B likely suppressed the proliferation, migration, and tube formation of vascular endothelial cells through dephosphorylation of vascular endothelial growth factor receptor 2. Conclusions Our study demonstrated that PTP1B negatively modulated the diabetic wound healing process by dephosphorylating the endothelial cell vascular endothelial growth factor receptor 2 and that the specific inhibitor of PTP1B might serve as a potential novel therapeutic tool for diabetic wound healing.

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Wound healing potential of topical bacteriophage therapy on diabetic cutaneous wounds

Cited by 100 publications

References 34 publications

Two Phages, phiIPLA-RODI and phiIPLA-C1C, Lyse Mono- and Dual-Species Staphylococcal Biofilms

Two Phages, phiIPLA-RODI and phiIPLA-C1C, Lyse Mono- and Dual-Species Staphylococcal Biofilms

Using viruses as nanomedicines

Protein Tyrosine Phosphatase 1B Impairs Diabetic Wound Healing Through Vascular Endothelial Growth Factor Receptor 2 Dephosphorylation

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