Polymyxin D2

Introduction: Surfactin (SF) is a cyclic lipopeptide that has potent mucosal adjuvant properties. However, immunological mechanisms of SF adjuvant action have not yet been elucidated. As some cyclic lipopeptides, such as polymyxin, can stimulate histamine release from mast cells, we hypothesized that mast cell activation is critical for SF adjuvanticity. Methods/results: We observed that following intranasal immunization with ovalbumin (OVA) plus SF, the titers of the OVA-specific antibody (Ab) in the mucosal secretions and plasma of mast cell-deficient mice were significantly lower than those in congenic normal mice, although OVA-specific Ab did not entirely disappear from mast cell-deficient mice. SF induced degranulation of mast cells and release of histamine in vitro. To investigate whether SF stimulated mast cells in vivo, we measured body temperature of mice immunized intranasally with OVA plus SF because histamine level affects body temperature. Following immunizations, body temperature of immunized congenic normal mice transiently decreased, whereas body temperature of mast cell-deficient mice did not change. Plasma levels of OVA-specific IgE Ab were not significantly different in mast cell-deficient and congenic normal mice. These findings suggest that SF directly affected mast cells in an IgE Ab-independent fashion. Furthermore, we analyzed the effects of SF on MC/9 mast cells cultured in vitro. MC/9 cells stimulated by SF released not only histamine but also leukotriene B4 and prostaglandin D2 . Moreover, SF up-regulated mRNA expression levels of Tnf, Ccr5, and Il4 genes in mast cells. These cytokines may play a facilitating role in OVA-specific immune responses in mice. Conclusion: Overall, our results showed that mast cell activation partially mediated SF adjuvanticity.

In this paper, 26 natural polymyxin components and a new derivative S2 were synthesized, and their differences in efficacy and toxicity have been investigated. Almost all of the synthesized components showed strong activity against both susceptible and resistant strains of E. coli, K. pneumoniae, P. aeruginosa, and A. baumannii. The toxicities were obviously different between the components. Only some of the components were tested for toxicity in vivo. Compounds E2, E2-Val, A2, M2, D2, and S2 showed obviously lower renal cytotoxicity and acute toxicity than polymyxins B and E. The in vivo nephrotoxicity of E2, M2, and S2 was similar to that of polymyxin E. Compound S2, with four positive charges, was especially interesting as it possessed both increased efficacy and decreased toxicity. The SAR and toxicity studies indicated that further structural modification could concentrate on polymyxin S. The results also indicated that S2 could be a new drug candidate.

Background: The multidrug-resistant (MDR) Acinetobacter baumannii (A. baumannii) has become one of the most important pathogens of nosocomial infection due to widespread use of broad spectrum antimicrobial drugs and immunosuppressor therapy. As polymyxins resistance emerges, developing novel effective antibacterial agents capable of overcoming multidrug resistance is urgently needed. Methods: In this study, biodegradable triblock copolymers of polyethylene glycol (PEG), guanidinium-functionalized polycarbonate and polylactide, PEG-PGC20-PLLA20 (L2) and PEG-PGC20-PDLA20 (D2), were utilized as antibacterial agents. Results: The copolymers self-assemble into micellar nanoparticles (L/D2), and exhibit broad-spectrum antibacterial activity against 20 clinically isolated multidrug-resistant A. baumannii strains. L/D2 had more rapid killing kinetics than conventional antibiotics imipenem and ceftazidime, and exhibited potent anti-biofilm activity. Repeated use of L/D2 did not induce drug resistance. From scanning electron microscopy and nucleic acid release analyses, L/D2 showed membrane-lytic mechanism. We also demonstrated that L/D2 was synergistically active with imipenem against MDR A. baumannii strains. Additionally, strong synergistic antibacterial activity was also observed for the combined use of L/D2 and imipenem in a MDR A. baumannii abdominal infection mouse model. Conclusions: Therefore, the combination of L/D2 and imipenem might be an alternative option for the prevention of nosocomial infection caused by A. baumannii.