The product that will result from this proposal will be a potent biological regulator of innate immunity, 1- peptidyl-2,3-diacylglyceride (PDAG), for use in the prevention of hospital-acquired (nosocomial) infections in highly-susceptible patient populations. Nosocomial infection is a rapidly growing cause of morbidity and mortality in U.S. hospitals and nosocomial bloodstream infections have been estimated to be the eighth leading cause of death in the United States. The burden of the nosocomial infection rate is largely borne by patients who are undergoing prolonged invasive procedures (e.g. indwelling catheterization, ventilation) and/or who are undergoing immunosuppressive therapies or are characterized by immuno-compromising risk factors (e.g. neonates, the elderly, chemo- or radiotherapy patients, HIV/AIDS patients). The increasing incidence of nosocomial infections can be attributed in large part to the alarming rate at which pathogens are acquiring resistance to antibiotics, such as methicillin-resistant Staphylococcus aureus (MRSA). This problem is compounded by the fact that, in over thirty years, only two new classes of antibiotics have reached the market. It is clear that prophylactic strategies that provide alternatives or adjuncts to conventional antibiotics are urgently needed to protect highly-susceptible patient groups from nosocomial infection. We have recently identified that PDAG is an immunomodulator. Our hypothesis is that PDAG is an activator of innate immune responses to cell injury, and that its effects are mediated by activation of monocyte derived macrophage. Moreover, we believe that PDAG is the mammalian equivalent of the macrophage activating lipopeptide MALP- 2. Here, we propose to develop a therapeutic immunoregulatory biological agent, based on the structure of PDAG, for use in protecting highly susceptible patient groups from nosocomial infections. PDAG is well-suited for this indication since, unlike existing immune regulating therapies, it is a regulator of the non-specific innate immune response, the first line of host defenses. Our preliminary data demonstrate that, while PDAG is not itself bactericidal, it induces a phagocytic cytokine/chemokine profile in human leukocytes, it up-regulates at least two downstream effectors - opsonic acute phase proteins and IgM, and it confers protection in an animal model of bacteremia. These observations strongly suggest that PDAG has considerable utility as a novel, immunoregulatory, prophylactic, anti-infective agent. To initiate development of PDAG for human use, and to demonstrate the feasibility of the final product, we will manufacture and formulate PDAG in a drug product (Aim I), we will further delineate PDAG's immunological mode of action (Aim II), determine a therapeutic index, demonstrate that PDAG does not induce a cytokine storm, and show the efficacy of the formulated drug product in a MRSA SSTI that is directly relevant to hospital acquired infections (Aim III).
This proposal will reduce the growing incidence of hospital-acquired infections by developing a drug-like compound that can be used to protect highly susceptible patients. Hospital-acquired infections often involve bacteria that are resistant to conventional antibiotics. The product being developed in this proposal will reduce the need to use antibiotics, because it works by stimulating the phagocytic activity of the human innate immune system.
| Thacker, James D; Balin, Brian J; Appelt, Denah M et al. (2012) NLRP3 inflammasome is a target for development of broad-spectrum anti-infective drugs. Antimicrob Agents Chemother 56:1921-30 |
