Two main projects are currently being undertaken by the Ghiladi research group. These include research efforts directed at understanding i) metalloprotein structure-function relationships in multifunctional hemoproteins including dehaloperoxidase (DHP) and catalase-peroxidase (KatG), ii) antimicrobial photodynamic therapy. A brief synopsis of each is given below as one can read the representative publications for details.
Mechanistic Investigations of Dehaloperoxidase
From our initial study in early 2009 (Biochem., 2009, 48, 995-1005), the work on understanding the multifunctional hemoprotein dehaloperoxidase (DHP) has gone in several new directions. Our research was the first study of the DHP B isoenzyme, both structurally (Acta Cryst. 2010, D66, 529-538) and spectroscopically (Biochem. 2010, 49, 6600-6616; J. Am. Chem. Soc. 2010, 132, 17501-17510). We have elucidated the mechanism of activation of this globin-peroxidase when starting from the oxyferrous state (Biochem. 2011, 50, 5999-6011), and have published high profile papers on DHP (J. Biol. Chem., 2013, 288, 33470–33482 and J. Am. Chem. Soc., 2014, 136, 7914−7925), the latter of which demonstrated new activities in DHP that represent the future of this protein. We have also identified the reactivity of DHP with nitrophenols (Biochemistry 2016, 55, 2465–2478), azole pollutants (Biochemistry 2017, 56, 2294-2303), and pyrrole compounds (Catal. Sci. Technol. 2017, 7, 3104-3118), all of which represent new substrates and new directions to explore with DHP.
Antimicrobial Photodynamic Therapy
Hospital acquired infections, in particular, highlight the issue of adherence and survival of bacteria on surfaces leading to an increase in the proliferation and transmission of bacteria. Specifically, antibiotic-resistant bacteria are a rising threat to human health. According to the Centers of Disease Control and Prevention, about 1.7 million healthcare associated infections cause upwards of 99,000 deaths annually in the United States, representing the sixth leading cause of mortality in the US and an increasing economic burden on an already strained healthcare system. The pathogens that give rise to HAIs are capable of surviving for prolonged periods in hospital environments (linens, drapes, bed rails) and on the hands of healthcare workers. Depending on the strain, Acinetobacter baumannii, Mycobacterium tuberculosis, and Staphylococcus aureus all have been shown to remain viable on dry, abiotic surfaces for upwards of 6 months. Consequently, more research into effective surface disinfection and alternative materials (fabrics, plastics or coatings) with antimicrobial properties is needed. To that end, we have been increasing our efforts towards the synthesis of porphyrin-peptide conjugates for targeted PDT, expanding our studies to include other bacteria, as well as collaborative work with the Argyropoulos (Dept. of Forest Biomaterials), Scholle (Dept. of Biological Sciences), and Zhang (Department of Textile Engineering) labs in developing antimicrobial materials based on cellulose (Biomacromolecules 2015, 16, 2482-2492) and polyacrylonitrile (Nanomaterials 2016, 6, 77), as well as solution studies using PDT in antimicrobial (Molecules 2015, 20, 10604-10621, invited) and anticancer applications (Bioconjugate Chemistry, 2016, 27, 1227-1235; ACS Biomater. Sci. Eng. 2016, 2, 838-844). Recent studies include the use of fluorinated polymer-photosensitizer conjugates for improved PDT efficacy (Polymer Chemistry 2017, 8, 3195-3202), as well as collaborative work with the labs of Profs. Qufu Wei and Qingqing Wang (Jiangnan University, China).