Disarming Pore-Forming Toxins with Biomimetic Nanosponges in Intraocular Infections

• Published in: mSphere Vol. 4; no. 3
• Main Authors: Coburn, Phillip S, Miller, Frederick C, LaGrow, Austin L, Land, Craig, Mursalin, Huzzatul, Livingston, Erin, Amayem, Omar, Chen, Yijie, Gao, Weiwei, Zhang, Liangfang, Callegan, Michelle C
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 15-05-2019
• Subjects: Animals; antibiotic; Antibiotics; Bacillus cereus; Bacteria; Bacterial Toxins - antagonists & inhibitors; Biomimetic Materials; Blindness; Corticosteroids; Endophthalmitis; Enterococcus faecalis; Enucleation; Erythrocytes - chemistry; Experiments; Eye; Eye Infections, Bacterial - drug therapy; Gatifloxacin; Gatifloxacin - therapeutic use; Gram-Positive Bacterial Infections - drug therapy; Health sciences; Histology; infection; Methicillin; Methicillin-Resistant Staphylococcus aureus - drug effects; Mice; Mice, Inbred C57BL; Multidrug resistance; nanoparticle; Nanostructures - chemistry; Nanostructures - therapeutic use; Nanotechnology; Pathogenesis; Pathogens; Polylactic Acid-Polyglycolic Acid Copolymer - chemistry; Polymers - chemistry; Rabbits; Retention; Retina; Standard deviation; Staphylococcal Infections - drug therapy; Staphylococcal Infections - microbiology; Staphylococcus aureus; Staphylococcus aureus - drug effects; Staphylococcus infections; Streptococcus infections; Streptococcus pneumoniae; Therapeutics and Prevention; Toxins; Trauma; United States > US; Oklahoma; California; antibiotic; eye; nanoparticle; infection; endophthalmitis
• ISSN: 2379-5042; 2379-5042
• DOI: 10.1128/mSphere.00262-19

Intraocular infections are prevalent after traumatic injuries or after common ocular surgeries. Infections cause inflammation that can damage the retina and architecture of the eye, often resulting in poor visual outcomes. Severe cases may result in blindness or require enucleation of the eye. Treatments for intraocular infections include intravitreal antibiotics and corticosteroids or surgical vitrectomy in serious cases. The increase in multidrug-resistant infections calls for novel treatment options. In the present study, a biomimetic erythrocyte-derived nanosponge was tested for the ability to neutralize pore-forming toxins from the most frequent Gram-positive bacterial causes of intraocular infections (
,
,
, and
). Nanosponge pretreatment of supernatants reduced hemolytic activity
In a murine sterile endophthalmitis model, nanosponge pretreatment of injected supernatants resulted in greater retinal function and less ocular pathology compared to that in eyes injected with untreated supernatants from all pathogens except methicillin-resistant
In a murine bacterial endophthalmitis model, treatment with gatifloxacin and gatifloxacin-nanosponges reduced intraocular bacterial burdens, except in the case of methicillin-sensitive
For all pathogens, eyes in both treatment groups showed decreased ocular pathology and inflammation. Overall, reductions in retinal function loss afforded by gatifloxacin-nanosponge treatment were significant for
,
, and methicillin-resistant
but not for
and methicillin-sensitive
These results suggest that clinical improvements in intraocular infections following nanosponge treatment were dependent on the complexity and types of toxins produced. Nanosponges might serve as an adjunctive therapy for the treatment of ocular infections.
Endophthalmitis is a blinding consequence of bacterial invasion of the interior of the eye. Because of increases in the numbers of ocular surgeries and intraocular injections, the incidence of endophthalmitis is steadily increasing.
,
,
, and
are leading causes of infection following ocular procedures and trauma and are increasingly more difficult to treat due to multidrug resistance. Each of these pathogens produces pore-forming toxins that contribute to the pathogenesis of endophthalmitis. Treatment of these infections with antibiotics alone is insufficient to prevent damage to the retina and vision loss. Therefore, novel therapeutics are needed that include agents that neutralize bacterial pore-forming toxins. Here, we demonstrate that biomimetic nanosponges neutralize pore-forming toxins from these ocular pathogens and aid in preserving retinal function. Nanosponges may represent a new form of adjunct antitoxin therapy for serious potentially blinding intraocular infections.