Table 1.
New therapeutic alternatives evaluated against F. tularensis infection.
| Drug | Mechanism of action/target | Activity on F. tularensis | References |
|---|---|---|---|
| NEW ANTIBIOTICS | |||
| Ketolides | Inhibit protein synthesis by interacting with the peptidyl-transferase site of the bacterial 50S ribosomal subunit. | Effective in vitro against French isolates of F. tularensis subsp. holarctica | Gestin et al., 2010 |
| Tigecycline | Inhibits protein translation by binding to the 30S ribosomal subunit and blocking entry of amino-acyl tRNA molecules into the A site of the ribosome | Effective in vitro against Hungarian F. tularensis subsp. holarctica | Kreizinger et al., 2013b |
| Grepafloxacin | Inhibit DNA synthesis by targeting DNA gyrase and topoisomerases | Highly active in vitro against American and | Ikaheimo et al., 2000 |
| Trovafloxacin | Austrian F. tularensis subsp. tularensis and subsp. holarctica strains | Johansson et al., 2002 | |
| Sparfloxacin | Gatifloxacin effective in vivo in a BALB/c mouse model of F. tularensis Schu S4 infection | Tomaso et al., 2005 | |
| Gatifloxacin | Piercy et al., 2005; Steward et al., 2006 | ||
| Linezolide | Inhibits the initiation process of protein synthesis | Effective in vitro against Turkish strains, Not effective against F. tularensis strains isolated in Hungary or in North America | Yesilyurt et al., 2011 Johansson et al., 2002 |
| ANTIMICROBIAL PEPTIDE | |||
| LL-37 | Stimulates the innate immune response, increases in the production of IL-6, Il-12, IFN-gamma, and MCP-1 | Moderately and transiently effective in a murine model of LVS-induced pneumonia | Flick-Smith et al., 2013 |
| OTHER MODULATOR OF INNATE IMMUNE RESPONSE | |||
| IL-12 | Activates Th1 and NK cells and induces the production of IFN-gamma | Improves the clinical outcome and survival of animals infected with F. novicida, when co-administrated with gentamicin. | Pammit et al., 2004 Kirimanjeswara et al., 2008 |
| AGP | Synthetic TLR4 agonist, increases the amount of intrapulmonary cytokines and chemokines | Reduced bacterial replication in the lungs, liver and spleen, and increased survival of animals infected with F. novicida | Lembo et al., 2008 |
| CpG | TLR9 activator, indirectly activates NK cells resulting in cytokines and NO production | Better survival of mice infected with F. tularensis LVS, but no effect in mice with F. tularensis SCHU4 pneumonia | Elkins et al., 2009 Rozak et al., 2010 |
| poly(I:C) | Synthetic double stranded RNA analog, TLR3 activator, induces an early and effective innate immune response | Better survival of mice infected with F. tularensis LVS or Schu S4 Reduction in replication of F. tularensis within human monocyte-derived macrophages | Pyles et al., 2010 |
| Galantamine | Influences the immune response via the cholinergic anti-inflammatory pathway by up-regulating IFN-gamma production and down-regulating IL-6 production | Reduced mortality rates in mice infected with F. tularensis LVS | Pohanka et al., 2012 |
| Acai PS | Enhances Th1 cell-related immunity | Increased survival of mice infected with F. tularensis Schu S4 | Skyberg et al., 2012 |
| SPECIFIC ANTIBODIES | |||
| Monoclonal antibodies | Monoclonal antibodies against the LPS of F. tularensis LVS | Successfully used to treat LVS-induced pneumonia; No effect on mice infected with F. tularensis Schu S4 | Lu et al., 2007 Kirimanjeswara et al., 2008 Savitt et al., 2009 |
| Immune sera | Immune sera from mice infected via intra-nasal Schu S4 challenge, and then treated with levofloxacin Sera containing abundant immunoglobulin IgG2a | Protective in mice infected with F. tularensis Schu S4, when administered 24 h post-infection | Klimpel et al., 2008 |
| Anti-MPF IgM and IgG antibodies | Antibodies directed against the membrane protein fraction (MFP) of F. tularensis Schu S4 | Successfully used to treat mice infected with F. tularensis Schu S4 when combined with gentamicin | Sutherland et al., 2012 |