Repurposing sunscreen as an antibiotic: zinc-activated avobenzone inhibits methicillin-resistant Staphylococcus aureus.

Methicillin-resistant Staphylococcus aureus (MRSA) is a major healthcare concern with associated healthcare costs reaching over ${\$}$1 billion in a single year in the USA. Antibiotic resistance in S. aureus is now observed against last line of defense antibiotics, such as vancomycin, linezolid, and daptomycin. Unfortunately, high throughput drug discovery approaches to identify new antibiotics effective against MRSA have not resulted in much tangible success over the last decades. Previously, we demonstrated the feasibility of an alternative drug discovery approach, the identification of metallo-antibiotics, compounds that gain antibacterial activity only after binding to a transition metal ion and as such are unlikely to be detected in standard drug screens. We now report that avobenzone, the primary active ingredient of most sunscreens, can be activated by zinc to become a potent antibacterial compound against MRSA. Zinc-activated avobenzone (AVB-Zn) potently inhibited a series of clinical MRSA isolates [minimal inhibitory concentration (MIC): 0.62-2.5 µM], without pre-existing resistance and activity without zinc (MIC: >10 µM). AVB-Zn was also active against clinical MRSA isolates that were resistant against the commonly used zinc-salt antibiotic bacitracin. We found AVB-Zn exerted no cytotoxicity on human cell lines and primary cells. Last, we demonstrate AVB-Zn can be deployed therapeutically as lotion preparations, which showed efficacy in a mouse wound model of MRSA infection. AVB-Zn thus demonstrates Zn-activated metallo-antibiotics are a promising avenue for future drug discovery.

Pyrazolyl Thioureas and Carbothioamides with an NNSN Motif against MSSA and MRSA.

A novel series of copper-activatable drugs intended for use against methicillin-sensitive Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA) were synthesized, characterized, and tested against the MSSA strain Newman and the MRSA Lac strain (a USA300 strain), respectively. These drugs feature an NNSN structural motif, which enables the binding of copper. In the absence of copper, no activity against MSSA and MRSA at realistic drug concentrations was observed. Although none of the novel drug candidates exhibits a stereocenter, sub-micromolar activities against SA Newman and micromolar activities against SA Lac were observed in the presence, but not in the absence, of bioavailable copper. Copper influx is a component of cellular response to bacterial infections, which is often described as nutritional immunity.

Protease-Activated Sensors for In Vivo Imaging of Cell Populations.

Biosensors are important devices that can be used to obtain information from within a living organism. They can be implanted within living tissues in order to continuously monitor for changes. This allows for personalized, noninvasive medicine, since a baseline can be more accurately established and any deviations, even slight, can be detected. These devices have applications in the treatment of diseases such as diabetes and cancer, as well as the study of pathways of interest and tailored drug dosing. Proteases within the tumor microenvironment can be studied in vivo in order to indicate the effectiveness of treatments received. This unprecedented real-time information is extremely valuable as it can be used to alter the course of treatment accordingly.

Antibody-Targeted Magnetic Nanoparticles to Track Immune Cells In Vivo.

Brain tumors can prove difficult to diagnose and successfully treat. Gliomas, and in particular glioblastomas, are the most common type of primary brain tumor. The most difficult part about treating these tumors is the fact that they are able to migrate through the extracellular space inside the brain. Recurrence is also highly possible due to their invasive nature, leading to the destruction of nearby tissues. The migratory nature of these tumors makes imaging difficult. To combat this, antibodies can be conjugated to the surface of nanoparticles such as superparamagnetic iron oxide (SPIO) nanoparticles to help target the immune cells. This creates a unique bimodal system that is able to detect the brain cancer cells and assist tumor surgery in conjunction with magnetic resonance imaging (MRI).