Eric Oldfield

The work in our group is currently focused on two areas: anti-infective drug leads and anti-cancer drug leads. As is well known, there is a public health crisis due to the spread of drug resistant bacteria. One way to help address this problem is to use combination therapies. Another is that stimulating the first responders-gamma delta T cells, neutrophils and macrophages, could be effective. Targeting virulence factors is also of interest, offering high selectivity, as is targeting "physical" properties, such as membrane lipid bilayer permeability, as with daptomycin. Also, some very well-known drugs—rather than having a single target—have multiple targets. For example, penicillin targets families of penicillin-binding proteins, and fluoroquinolones such as ciprofloxacin target DNA-binding proteins. We hypothesize that isoprenoid biosynthesis enzymes, prenylsynthases and prenyltransferases, involved in cell wall and quinone biosynthesis, represent a new generation of targets whose inhibition will lead to new drug leads that synergize with existing antibiotics. Plus, in some cases they will also affect membrane permeability, virulence and innate immunity. Our targets are undecaprenyl diphosphate synthase (UPPS), undecaprenyl diphosphate phosphatase (UPPP), farnesyl diphosphate synthase (FPPS), and octaprenyl/heptaprenyl diphosphate synthase (OPPS/HepPPS). UPPS lies between FPPS and UPPP in the cell wall biosynthesis pathway and we have leads that inhibit [UPPS+UPPP] or [UPPS+FPPS], some active in vivo, that also synergize with other antibiotics. We will also investigate FPPS and OPPS/HepPPS since dual-target inhibition of these will inhibit quinone biosynthesis and thus, bacterial bioenergetics. In one area, we focus on developing anionic prenyl synthase inhibitors based on recently discovered phosphonate/bisphosphonate and carboxylate leads, developing the (pre-) prodrug approach used in many antivirals for use in antibacterials. In a second area, we focus on developing cationic prenyl synthase inhibitors based on recently discovered inhibitors that target FPPS, UPPS and UPPP. And in a third area we are investigating prenyl synthase mechanisms of action and inhibition; toxicity; mutation frequencies; and synergy with compounds such as beta-lactams, vancomycin and fosmidomycin.

The second area of interest in in anti-cancer drug discovery. Here the objective is to develop novel anti-cancer drugs that target metastatic disease that can also function as cancer vaccine adjuvants. According to the National Cancer Institute’s Cancer Statistics Review (1975-2013), there were 14.1 million men and women alive in the United States who had been diagnosed with cancer of all sites, 6.6M men and 7.5M women, with breast, lung and prostate cancers making major contributions to morbidity and mortality. These cancers typically metastasize to bone and these bone symptoms are treated with a class of drugs called bisphosphonates. These drugs are very polar and bind to bone mineral and inhibit bone degradation by osteoclasts. In recent work, it has been found that bisphosphonates, in particular zoledronate, also have a remarkable "adjuvant" effect in combination with aromatase inhibitors in breast cancer, decreasing the recurrence of disease (at any site), although mechanisms of action have not been reported. Many mechanisms for bisphosphonate activity have been proposed including direct tumor killing, γδ T cell activation, macrophage M2 (pro- tumor) to M1 (antitumor) phenotype switching, as well as anti-angiogensis and anti-invasiveness. In addition, bisphosphonates are known to have effects as adjuvants, in vaccines. Since there seem to be so many diverse effects of bisphosphonates, we hypothesize that there could be a heretofore missing link-or missing links-that might help explain their diverse activity. In particular, we propose that multiple signaling pathways are involved in which prenylation, kinase inhibition, and adenine nucleotide translocase/AMPactivated AMP kinase/mTOR can all be involved. Our objective is to synthesize a broad range of novel non-nitrogen-containing bisphosphonates and test them for activity as cancer vaccine adjuvants, and for activity in tumor growth inhibition in vivo. We are also interested in a second class of targets, lysyl oxidases, Cu-proteins whose inhibition affects signaling through the EGFR pathway that contributes to tumor metastasis and are using modern multi-dimensional EPR techniques to probe their structure, and inhibition.