October 11, 2018
Purdue researchers hope deadly MRSA superbugs take the bait
Published research paper reports new photoactive bacteria bait may help in fight against MRSA infections.
WEST LAFAYETTE, Ind. – Purdue University researchers are testing whether a light-active version of heme, the molecule responsible for transporting oxygen in blood circulation, may help people infected with MRSA.
The World Health Organization identifies MRSA as one of about a dozen antibiotic “superbugs” that pose an enormous threat to human health.
WHO has listed methicillin-resistant Staphylococcus aureus, or MRSA, as one of six ‘high priority’ pathogens with an imminent threat to public health. The Centers for Disease Control and Prevention reports 80,461 people in the United States suffer severe MRSA infections a year and 11,285 die.
Anyone can get MRSA on their body from contact with an infected wound, or by sharing personal items such as towels or razors that are contaminated. However, patients in hospitals are especially vulnerable to MRSA infections.
“MRSA infections can cause severe problems for patients recovering from surgery,” said Alexander Wei, a professor of chemistry in the College of Science who is leading the research team. “The challenge that we face is that MRSA responds poorly to multiple antibiotics. Antimicrobial photodynamic therapy offers a promising alternative for combating MRSA in infected wounds.”
Photodynamic therapy, or PDT, involves a compound known as a photosensitizer, which can be activated by visible light to kill diseased cells or bacteria. PDT is a clinically proven method for fighting cancer but has not yet been developed for treating MRSA infections.
The discovery aligns with Purdue's Giant Leaps celebration, recognizing the university’s global advancements made in health, longevity and quality of life as part of Purdue’s 150th anniversary. This is one of the four themes of the yearlong celebration’s Ideas Festival, designed to showcase Purdue as an intellectual center solving real-world issues.
The photosensitizer developed at Purdue is called Ga-PpIX, and is an analog of heme. Ana Morales-de-Echegaray, the lead graduate research assistant on the project at the time, discovered that Ga-PpIX could be gobbled up by MRSA strains within seconds, leading to their rapid inactivation using a simple light-emitting diode (LED) array that is safe to use on human skin.
“Our discovery is part of a convergence on campus to develop drugs and get them to people in need as quickly as possible,” Wei said.
Wei and his collaborator Mohamed Seleem, a professor in Purdue’s College of Veterinary Medicine, are working closely with the Purdue Institute of Inflammation, Immunology and Infectious Disease and the Purdue Institute for Drug Discovery to determine if this kind of treatment could work for animals and with other types of skin infection.
The technology is patented through Purdue Office of Technology Commercialization, and the researchers are looking for partners to continue developing practical applications for the discovery.
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Rapid Uptake and Photodynamic Inactivation of Staphylococci by Ga(III)-Protoporphyrin IX
†Department of Chemistry and ‡Department of Comparative Pathobiology, Purdue University, West Lafayette, Indiana 47907, United States
ACS Infect. Dis., Article ASAP
Antimicrobial photodynamic therapy (aPDT) is a promising method for the topical treatment of drug-resistant staphylococcal infections and can be further improved by identifying mechanisms that increase the specificity of photosensitizer uptake by bacteria. Here we show that Ga(III)-protoporphyrin IX chloride (Ga-PpIX), a fluorescent hemin analog with previously undisclosed photosensitizing properties, can be taken up within seconds by Staphylococcus aureus including multidrug-resistant strains such as MRSA. The uptake of Ga-PpIX by staphylococci is likely diffusion-limited and is attributed to the expression of high-affinity cell-surface hemin receptors (CSHRs), namely iron-regulated surface determinant (Isd) proteins. A structure–activity study reveals the ionic character of both the heme center and propionyl groups to be important for uptake specificity. Ga-PpIX was evaluated as a photosensitizer against S. aureus and several clinical isolates of MRSA using a visible light source, with antimicrobial activity at 0.03 μM with 10 s of irradiation by a 405 nm diode array (1.4 J/cm2); antimicrobial activity could also be achieved within minutes using a compact fluorescent lightbulb. GaPpIX was not only many times more potent than PpIX, a standard photosensitizer featured in clinical aPDI, but also demonstrated low cytotoxicity against HEK293 cells and human keratinocytes. Ga-PpIX uptake was screened against a diverse panel of bacterial pathogens using a fluorescence-based imaging assay, which revealed rapid uptake by several Gram-positive species known to express CSHRs, suggesting future candidates for targeted aPDT.