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Protection against virulent pathogens that cause acute, fatal disease is often hampered by development of microbial resistance to traditional chemotherapeutics. Further, most successful pathogens possess an array of immune evasion strategies to avoid detection and elimination by the host. Development of novel, immunomodulatory prophylaxes that target the host immune system, rather than the invading microbe, could serve as effective alternatives to traditional chemotherapies. Here we describe the development and mechanism of a novel pan-anti-bacterial prophylaxis. Using cationic liposome non-coding DNA complexes (CLDC) mixed with crude  F. tularensis  membrane protein fractions (MPF), we demonstrate control of virulent  F. tularensis  infection  in vitro  and  in vivo . CLDC+MPF inhibited bacterial replication in primary human and murine macrophages  in vitro . Control of infection in macrophages was mediated by both reactive nitrogen species (RNS) and reactive oxygen species (ROS) in mouse cells, and ROS in human cells. Importantly, mice treated with CLDC+MPF 3 days prior to challenge survived lethal intranasal infection with virulent  F. tularensis . Similarly to  in vitro  observations,  in vivo  protection was dependent on the presence of RNS and ROS. Lastly, CLDC+MPF was also effective at controlling infections with  Yersinia pestis ,  Burkholderia pseudomallei  and  Brucella abortus . Thus, CLDC+MPF represents a novel prophylaxis to protect against multiple, highly virulent pathogens.

Effective, Broad Spectrum Control of Virulent Bacterial Infections Using Cationic DNA Liposome Complexes Combined with Bacterial Antigens