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Fighting Staphylococcus aureus infections with light and photoimmunoconjugates.

ABSTRACT: Infections caused by multidrug-resistant Staphylococcus aureus, especially methicillin-resistant S. aureus (MRSA), are responsible for high mortality and morbidity worldwide. Resistant lineages were previously confined to hospitals but are now also causing infections among healthy individuals in the community. It is therefore imperative to explore therapeutic avenues that are less prone to raise drug resistance compared with today's antibiotics. An opportunity to achieve this ambitious goal could be provided by targeted antimicrobial photodynamic therapy (aPDT), which relies on the combination of a bacteria-specific targeting agent and light-induced generation of ROS by an appropriate photosensitizer. Here, we conjugated the near-infrared photosensitizer IRDye700DX to a fully human mAb, specific for the invariantly expressed staphylococcal antigen immunodominant staphylococcal antigen A (IsaA). The resulting immunoconjugate 1D9-700DX was characterized biochemically and in preclinical infection models. As demonstrated in vitro, in vivo, and in a human postmortem orthopedic implant infection model, targeted aPDT with 1D9-700DX is highly effective. Importantly, combined with the nontoxic aPDT-enhancing agent potassium iodide, 1D9-700DX overcomes the antioxidant properties of human plasma and fully eradicates high titers of MRSA. We show that the developed immunoconjugate 1D9-700DX targets MRSA and kills it upon illumination with red light, without causing collateral damage to human cells.

SUBMITTER: Bispo M

PROVIDER: S-EPMC7710284 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Fighting Staphylococcus aureus infections with light and photoimmunoconjugates.

Bispo Mafalda M Anaya-Sanchez Andrea A Suhani Sabrina S Raineri Elisa J M EJM López-Álvarez Marina M Heuker Marjolein M Szymański Wiktor W Romero Pastrana Francisco F Buist Girbe G Horswill Alexander R AR Francis Kevin P KP van Dam Gooitzen M GM van Oosten Marleen M van Dijl Jan Maarten JM

JCI insight 20201119 22

Infections caused by multidrug-resistant Staphylococcus aureus, especially methicillin-resistant S. aureus (MRSA), are responsible for high mortality and morbidity worldwide. Resistant lineages were previously confined to hospitals but are now also causing infections among healthy individuals in the community. It is therefore imperative to explore therapeutic avenues that are less prone to raise drug resistance compared with today's antibiotics. An opportunity to achieve this ambitious goal coul ...[more]

PMID: 33048846

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Project description:Staphylococcus aureus (S. aureus) infections are important because of their increasing frequency, resistance to antibiotics, and high associated rates of disabilities and deaths. We examined the incidence and correlates of S. aureus infections following 219,958 major surgical procedures in a 5% random sample of fee-for-service Medicare beneficiaries from 2004-2007. Of these surgical patients, 0.3% had S. aureus infections during the hospitalizations when index surgical procedures were performed; and 1.7% and 2.3%, respectively, were hospitalized with infections within 60 days or 180 days following admissions for index surgeries. S. aureus infections occurred within 180 days in 1.9% of patients following coronary artery bypass graft surgery, 2.3% following hip surgery, and 5.9% following gastric or esophageal surgery. Of patients first hospitalized with any major infection reported during the first 180 days after index surgery, 15% of infections were due to S. aureus, 18% to other documented organisms, and no specific organism was reported on claim forms in 67%. Patient-level predictors of S. aureus infections included transfer from skilled nursing facilities or chronic hospitals and comorbid conditions (e.g., diabetes, congestive heart failure, chronic obstructive pulmonary disease, and chronic renal disease). In a logarithmic regression, elective index admissions with S. aureus infection stayed 130% longer than comparable patients without that infection. Within 180 days of the index surgery, 23.9% of patients with S. aureus infection and 10.6% of patients without this infection had died. In a multivariate logistic regression of death within 180 days of admission for the index surgery with adjustment for demographics, co-morbidities, and other risks, S. aureus was associated with a 42% excess risk of death. Due to incomplete documentation of organisms in Medicare claims, these statistics may underestimate the magnitude of S. aureus infection. Nevertheless, this study generated a higher rate of S. aureus infections than previous studies.

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Fighting Staphylococcus aureus infections with light and photoimmunoconjugates.

Publications

Fighting Staphylococcus aureus infections with light and photoimmunoconjugates.

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