Dermaseptin DMS-DA6 outperforms linezolid in resolving N. brasiliensis-induced actinomycetoma in mice

Actinomycetoma is a chronic infectious disease, recognized as a neglected tropical disease, primarily caused by the Gram-positive bacterium Nocardia brasiliensis in the Americas. This pathogen evades host microbicidal mechanisms by surviving and multiplying within macrophages, creating an immunosuppressive environment. Current antibiotic treatments are often expensive, prolonged, and toxic, with increasing reports of bacterial resistance. Host defense peptides, known for their inherent bactericidal and immunomodulatory properties, offer a promising alternative to address these significant therapeutic gaps.

Researchers evaluated the effects of DMS-DA6 in a mouse model of actinomycetoma induced by N. brasiliensis, comparing it to the conventional antibiotic linezolid. Infected mice were treated either twice weekly with DMS-DA6 12.5 mg/kg or every 12 hours with linezolid 25 mg/kg over a four-week period. Primary endpoints included assessment of inflammation and bacterial load in the footpad. Immune modulation was also evaluated by measuring IL-10, IL-1α, and IL-6 levels, and quantifying CD4+ and CD8+ T lymphocytes in the infected tissue.

Dermaseptin DMS-DA6 demonstrated superior efficacy in resolving N. brasiliensis-induced actinomycetoma compared to linezolid. Despite being administered at a lower dose and with significantly fewer injections, DMS-DA6 achieved a similar reduction in both inflammation and bacterial load within the infected footpad. This suggests a more favorable therapeutic index for the peptide. Furthermore, DMS-DA6 actively modulated the immune response during the chronic stage of infection. It influenced cytokine levels, specifically modulating IL-10, IL-1α, and IL-6, which are crucial mediators of inflammation and immune regulation.

DMS-DA6 is more effective at resolving the disease than linezolid, as it achieves a similar reduction in inflammation and bacterial load of the footpad at a lower dose and with fewer injections. The peptide also increased the abundance of key immune cells, specifically CD4+ and CD8+ T lymphocytes, in the infected footpad, indicating a robust cellular immune response. These findings collectively highlight DMS-DA6's potential as a potent antimicrobial and immunomodulatory agent.