β-lactamase enzyme-activated photosensitizer (β-LEAP). We aim to exploit drug resistance mechanisms to selectively
release photosensitizers (PSs) for a specific photodynamic antimicrobial effect and reduced host tissue damage.
Consequently, the fluorescence emission intensity of the PSs increases and allows for the detection of enzyme activity.
In this work we sought to evaluate β-LEAP for use as a sensitive molecular probe. We have reported the enzyme specific
antibacterial action of β-LEAP. Here we report the use of β-LEAP for the rapid functional definition of a β-lactamase.
Photodynamic therapy (PDT) as a treatment modality for infectious disease has shown promise. However, most of the
antimicrobial photosensitizers (PS) non-preferentially accumulate in both bacteria and host tissues, causing host tissue
phototoxicity during treatment. We have developed a new antimicrobial PDT strategy which exploits beta-lactam
resistance mechanism, one of the major drug-resistance bacteria evolved, to achieve enhanced target specificity with
limited host damage. Our strategy comprises a prodrug construct with a PS and a quencher linked by beta-lactam ring,
resulting in a diminished phototoxicity. This construct, beta-lactamase enzyme-activated-photosensitizer (beta-LEAP),
can only be activated in the presence of both light and bacteria, and remains inactive elsewhere such as mammalian
tissue. Beta-LEAP construct had shown specific cleavage by purified beta-lactamase and by beta-lactamase over-expressing
methicillin resistant <i>Staphylococcus aureus</i> (MRSA). Specific photodynamic toxicity was observed towards
MRSA, while dark and light toxicity were equivalent to reference strains. The prodrug design, synthesis and
photophysical properties will be discussed.
The photophysics and mechanisms of cell killing by photodynamic therapy (PDT) have been extensively studied in
recent years, and PDT has received regulatory approval for the treatment of a number of diseases worldwide. As the
application of this treatment modality expands with regard to both anatomical sites and diseases, it is important to
develop strategies for enhancing PDT outcomes. Our group has focused on developing targeting strategies to enhance
PDT for both cancerous as well as anti-microbial applications. In this article, we will discuss photosensitizer
modification and conjugation strategies for targeted antimicrobial photodynamic therapy.