Vaccine adjuvants are critical to improve the immunogenicity, efficacy, and durability of vaccines; however, their development has lagged behind that of vaccine antigens. Monophosphoryl lipid A (MPLA), a clinically approved adjuvant that stimulates Toll-like receptor 4 (TLR4), faces manufacturing challenges due to its complex and long synthesis. With the aim of simplifying the structure of MPLA while retaining its biological activity, we developed monosaccharide-based molecules FP18 and FP20Rha that activate TLR4 signaling. Both TLR4 agonists induced robust antibody activity against the model antigen, ovalbumin. Here, we report the potential of these TLR4 agonists to enhance the protective efficacy of the well-characterized OprF antigen against infection. OprF adjuvanted with FP18 showed reduced bacterial loads in lungs and spleens, relative to antigen alone in an acute pneumonia model. FP18-adjuvanted OprF also enhanced the production of anti-OprF antibodies and stimulated IFNγ and TNF in CD4 T cells, suggesting a Th1-skewed cellular immune response. These adjuvants have promise for accelerating the development of effective vaccines against and other infectious diseases.