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In what turned out to be one of the biggest accidents of all time, Scottish bacteriologist Alexander Fleming returned to his lab after a vacation in 1928 to find a clear area surrounding a piece of mold that had grown. infiltrated into a Petri dish full of Staphylococcus aureus (S. aureus), a common skin bacteria that he cultivated.
This region without bacterial growth was the unexpected birth of a medical miracle, penicillin, and would lead to the era of antibiotics. Now, in an article published today in the journal Science Translational Medicine, researchers at Johns Hopkins Medicine have announced another accidentally discovered, potentially breakthrough treatment that could provide an alternative immune solution to the danger of antibiotic-resistant bacterial infections.
And like Fleming’s surprise discovery, the bacteria in the note is once again S. aureus – but this time resistant to methicillin Staphylococcus aureus, the potentially fatal strain free from methicillin and other antibiotics, and better known by its acronym, MRSA.
The lead author of the article, Lloyd Miller, MD, Ph.D., former professor of dermatology, infectious diseases and orthopedic surgery at Johns Hopkins University School of Medicine, and now with Janssen Research and Development, said that the research team originally intended to investigate the mechanisms behind MRSA skin infections in mice with and without the ability to make interleukin-1 beta (IL-1β). This protein, converted to its active form by enzymes called caspases, boosts protective immunity by helping immune cells called neutrophils, monocytes, and macrophages fight bacterial infections.
“We gave the mice a blocker of all caspases [pancaspase inhibitor], a compound known as Q-VD-OPH, believed to make both sets of mice more vulnerable to MRSA infection, ”Miller said. “To our surprise, blocking the caspases had the opposite effect, resulting in rapid and remarkable elimination of the MRSA bacteria keeping immune cells alive and enhancing their protective function. “
Sensing that they might have accidentally discovered a way to combat bacterial “superbugs,” Miller and his colleagues conducted their latest study to confirm that the unexpected finding was no fluke.
The results were encouraging.
“A single oral dose of Q-VD-OPH reduced the size of MRSA skin lesions and rapidly cleared bacteria compared to the vehicle treated [given the carrier solution without Q-VD-OPH] and untreated mice, ”says lead author of the study, Martin Alphonse, Ph.D., postdoctoral researcher in dermatology at Johns Hopkins University School of Medicine. “And surprisingly, the treatment worked whether or not IL-1β was present – and without giving antibiotics.”
Researchers, explains Alphonse, have found that the pancaspase inhibitor reduces apoptosis – one of the three main methods the body uses to remove worn out or damaged cells – of neutrophils and monocytes, leaving them in large numbers. and better able to kill MRSA bacteria.
“It’s like a fire department where old fire trucks are kept on duty to help put out fires when otherwise they would have been taken out of service,” Miller explains.
The researchers also observed increased necroptosis – a second controlled cell death process similar to apoptosis – of macrophages, which are mature monocytes.
“The destruction of macrophages by necroptosis releases a large amount of tumor necrosis factor, or TNF, a protein that triggers the swarming of immune cells fighting bacteria in an infected area of the skin,” explains Alphonse.
Finally, the researchers tested whether Q-VD-OPH in mice could have broader activity against two other dangerous skin bacteria, Pyogenic streptococcus (the cause of several diseases, including scarlet fever, necrotizing fasciitis, and toxic shock syndrome) and Pseudomonas aeruginosa (often a threat to patients hospitalized on ventilators, with catheters or suffering from surgical wounds or burns). Targeting the body’s immune system against bacteria via inhibition of pancaspase – called “host-directed immunotherapy” – has been shown to be just as effective as for MRSA.
“It was an accidental discovery by Alexander Fleming that led to the golden age of antibiotics, but now it’s almost over because of the antibiotic resistant bacteria,” says Miller. “It seems fitting that another surprise in the lab could be the start of a second golden age, the use of host-directed immunotherapy.”
Along with Miller and Alphonse, the Johns Hopkins Medicine research team includes Jessica Rubens, Roger Ortines, Nicholas Orlando, Aman Patel, Dustin Dikeman, Yu Wang, Ivan Vuong, Daniel Joyce, Jeffrey Zhang, Mohammed Mumtaz, Halyun Liu, Qi Liu , Christine Youn, Garrett Patrick, Advaitaa Ravipati, Robert Miller and Nathan Archer.
Data from this study were included earlier this year in a US patent application (PCT / US2021 / 024889) through Johns Hopkins Technology Ventures for “the inhibition of caspase as an immunotherapy directed against bacterial infections ”.
The work was supported by grant T32AI052071 from the National Institute of Allergy and Infectious Diseases, and grants R01AR073665 and R01AR069502 from the National Institute of Arthritis, Musculoskeletal and Skin Diseases.
Miller is a full-time employee of Janssen Research and Development; received a grant from AstraZeneca, Pfizer, Boehringer Ingelheim, Regeneron Pharmaceuticals and Moderna Therapeutics; owns shares of Johnson & Johnson and Noveome Biotherapeutics; and has been a paid consultant for AstraZeneca, Armirall and Janssen Research and Development, all of which develop therapies against S. aureus and other pathogens.
None of the other authors have any financial disclosures or conflicts of interest related to this study.
Reference: Alphonse MP, Rubens JH, Ortines RV, et al. Inhibition of pan-caspase as a potential immunotherapy against MRSA and other bacterial skin infections. Sci. Trad. Med. 2021; 13 (601): eabe9887. of them: 10.1126 / scitranslmed.abe9887
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