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.
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.
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.
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