This proposal is in response to the NIAID Advanced Technology SBIR (PA-10-123) Funding Opportunity. This Phase I feasibility study is an advanced technology project with a clearly identified product that will result in a clinically relevant topical AM treatment modality. The award period and amount requested are guided by project needs and are in compliance with the issued guidelines. Every year, 57 million outpatient surgeries take place in the US, and among these, surgical site infections (SSIs) are the most common nosocomial infection. Studies show that as many as 55% of cases of SSI are preventable and that a reduction in SSI cases can contribute to saving ~4,431 lives and ~$1.6 billion in healthcare costs, annually. Various measures have been implemented however, prevention and treatment of SSI remains a major challenge due to emerging multi-drug resistance. Given the advantages of topical AM therapy in particular (lower costs, reduced potential for systemic toxicity, etc), there is a continuing need for enhancement of a clinically useful arsenal of topical AM therapies. One such therapy is Photodynamic Disinfection (PD). In a typical treatment, a non-toxic agent (the Photosensitizer or PS) is applied to the target wound. Upon illumination, the PS produces toxic reactive oxygen species (ROS) which effect microbial cell inactivation. Additionally, PD has been effective in reducing the potency of two important bacteria virulence factors (lipopolysaccharide and bacterial proteases). However, although results from in vitro testing do not suggest the need for any additional PS function, results from in vivo testing suggest the need for added selective PS binding to microbes over host cells for effective treatment. Currently, any observed selective binding is driven by an inherent difference in the uptake rates between bacteria and mammalian cells (PS uptake is faster in bacteria) which typically requires tight control over the drug-light interval (time lapse between PS administration and subsequent illumination). Inadequate control often results in poor efficacy. This has plagued the clinical utility of PD for years. The Lynntech-MGH team has pioneered an advanced PS technology platform with demonstrated potential to redefine the limits of PD efficacy, in vitro and in vivo. Our team has obtained a patent on a lead compound and has filed additional patent applications surrounding this platform technology. In this Phase I effort, our objective is to advance the field of AM PD and the current state of Lynntech'sPS platform (a clearly identified product) by coupling time- independent microbe binding selectivity with our lead PS structures for use in the prevention and treatment of SS. Microbe-selective peptides (MSP) will be conjugated with our PS, and the resulting conjugates will be evaluated for their AM and anti-LPS activity in vitro and in vivo.
Three specific aims will permit the completion of the proposed objective: 1) Develop a series of PS-MSP conjugates;2) Characterize PS-MSP conjugate activity in vitro, and;3) Evaluate PS-MSP AM PD efficacy in vivo. This effort is an integral part of a more comprehensive Technology Development Plan that is described in the Budget Justification.
Surgical site infections (SSIs) are now the second most common type of adverse event occurring in hospitalized patients: the nearly 1 million SSIs reported annually in the US account for an excess of 3.7 million hospital days and an estimated $1.6 billion in added costs, placing a significant burden on the US healthcare system. As such, there is a continuing need for enhancement of a clinically useful arsenal of topical antimicrobial (AM) therapies to counter the rapid emergence of antibiotic resistant organisms that cause SSI. The broader impact of this research that aims to advance a leading treatment modality (AM Photodynamic Disinfection) is the potential reduction of SSI and reduction in costs to the US healthcare system.