Novel antimicrobial phototherapy against emerging infectious diseases

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Research by: The Jikei University School of Medicine located in Tokyo, Japan and founded in 1881 is today one of the three major private medical schools in Japan. This cutting-edge study was done in close collaboration with Professor Hisataka Kobayashi’s Laboratory of Molecular Theranostics at National Cancer Institute.

Modulight products: ML6500 (689 nm, 3 W)

 

Dr. Makoto Mitsunaga, M.D., PhD

 

Dr. Tadayuki Iwase, PhD

 

Laser use: Photoimmunotherapy and photochemotherapy of cancer (pancreatic, breast, gastric) and infectious diseases both in vitro and in vivo.

Link to the study:

 

Motivation of the study

Discovery of new antimicrobial agents has been one of the most impactful feats of modern medicine and has saved numerous lives from fatal infections. However, antimicrobial resistance (AMR), which occurs when bacteria, viruses, fungi, or parasites develop over time and stop responding to medicines, poses a major threat to the success of modern medicine. AMR has been declared as one of the major global public health threats which means that therapies that could selectively eliminate pathogens irrespective of drug resistance status without harming host’s own tissues are now in greater need than ever. To address this issue, a multidisciplinary consortium of researchers was assembled and novel photoimmuno-antimicrobial strategy (PIAS) was developed.

Photoimmuno-antimicrobial Strategy (PIAS)

The PIAS platform consists of target-specific antibody conjugated to IRDye700DX. IRDye700DX has been shown to be safe and effective as anticancer therapy in patients with recurrent H&N cancer. The mechanism of PIAS is different from photodynamic therapy or traditional antimicrobials. After its administration as a solution to the infected area, it binds to the target pathogen and is locally activated by NIR illumination. The structural change of the IRDye700 generates mechanical stress that disrupts the binding of the pathogen to its target. PIAS is highly target-specific therapy and could be applied against broad range of pathogens (bacteria, fungi, viruses) by switching antibodies against appropriate pathogenic targets.

Antibody conjugated to IRDye700 binds to the target pathogen (bacteria, fungi or virus).

IRDye700 is activated by ML6500 series laser (689 nm, 330 mW/cm2, 50J/cm2).

Structural change of the activated IRDye700 generates mechanical stress and damages the binding sites of the target pathogen.

Disruption and clearance of the target pathogen.

The above schematics are reproduced from the original publication.

 

 

Experiments

PIAS was tested in vitro against many pathogens such as MRSA, fungal pathogen Candida albicans, and viral particles by switching antibodies against appropriate pathogenic targets.

PIAS was next studied in vivo using cotton rats with intranasal MRSA infection. Rats received intranasally S. aureus-targeted conjugate followed by 689 nm illumination 1h later using ML6500 series laser (0-50 J/cm2). Bacterial viability was then determined from the nares of the rats by plating samples to agar plates.

In another experiment, mice with intraperitoneal MRSA infection were treated with PIAS topical illumination (689 nm, 50 J/cm2), PIAS without illumination, PBS, or antibiotics (VCM/RFP) and monitored for 7 days. Fecal samples were collected from mice and 16S rRNA analysis was performed to investigate effects on intestinal microflora.

 

 

 

Mice with intraperitoneal MRSA infection were treated with photoimmuno-antimicrobial strategy (PIAS). Topical illumination carried out with ML6500 series 689 nm laser.

 

Results

PIAS-treated pathogens were effectively eradicated upon NIR illumination. The efficacy of PIAS was dependent on the NIR light dose, 50 J/cm2 eradicating all MRSA from the rat nasal tract (Figure 1). PIAS also saved all mice from fatal MRSA infections, similar to VCM+RFP antibiotics and even more effectively than VCM antibiotics alone (Figure 2). Unlike the antibiotics, PIAS acted selectively on the target pathogen and did not affect host’s normal intestinal microflora (Figure 3). Also generation of microbial resistance, common problem with antibiotics, was not observed with PIAS.

Figure 1. MRSA from nasal tract of rats treated with 0, 10, or 50 J/cm2 NIR laser light.

Figure 2. Effects of PIAS and antibiotics on survival of mice infected with intraperitoneal fatal MRSA infection.

 

Figure 3. Effect of PIAS and antibiotics on intestinal microflora of mice.

The above figures are reproduced from the original publication.

 

 

Conclusions:
The results suggest that PIAS is a promising novel anti-infection strategy that could be used against different threating pathogens, such as MRSA or COVID-19, based on the specificity of the antibody used. Compared to antibiotics, the specificity of this phototherapy can reduce unwanted side effects like reduction of abundance of host’s normal microflora. PIAS also does not seem to lead to antimicrobial drug resistance, which is growing problem with many classes of antibiotics. These properties of PIAS appear to be ideal for anti-infective therapy.

 

Related Modulight products and Services

 

Related Publications

A flexible target-specific anti-infection therapeutic platform that can be applied to different microbial species
Makoto Mitsunaga, Kimihiro Ito, Takashi Nishimura, Hironori Miyata, Yoshimitsu Mizunoe, Hisataka Kobayashi, Tadayuki Iwase
bioRxiv, 2020

 

 

 

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