Dermaseptin DMS-DA6, a promising alternative to conventional antibiotic in the treatment of N. brasiliensis induced actinomycetoma

Abstract

Actinomycetoma is a chronic infectious disease recognized by the World Health Organization as a neglected tropical disease. In the Americas, the most common etiologic agent is the Gram-positive bacterium, Nocardia brasiliensis. It is a facultative intracellular pathogen that can multiply and survive within macrophages, evading microbicidal mechanisms by inducing an immunosuppressive environment. Current antibiotic treatments are expensive, prolonged, and toxic, and bacterial resistance has been reported. Host defense peptides, known for their bactericidal and immunomodulatory effects, and their ability to induce poor bacterial resistance due to their direct effect on the bacterial membrane, represent a novel therapeutic approach. Recently, DMS-DA6, a dermaseptin isolated from the Mexican tree frog, Pachymedusa dacnicolor, has been shown to exert strong activity against Gram- positive bacteria, including multidrug-resistant strains. Our study evaluated the effects of DMS-DA6 in a N. brasiliensis-induced actinomycetoma mouse model in comparison with the ones observed with the conventional antibiotic linezolid. Infected mice were treated either twice a week with this peptide at a dose of 12.5mg/kg or every 12 hours with linezolid at a dose of 25 mg/kg over a three-week period. Our findings suggest that treatment with DMS-DA6 is more effective in resolving the disease than linezolid, as it induces a similar reduction in the volume of inflammation and bacterial load in the infected area at a lower dose and with fewer injections. These findings highlight the potential of DMS-DA6 as an innovative addition to current therapy. Author SummaryActinomycetoma is a chronic infectious disease induced by Gram-positive bacteria and listed as a neglected tropical disease that produces severe tissue deformation, and family, social, and economic problems. Current treatment takes years, is expensive, and induces undesirable effects and bacterial resistance, leading to amputation of extremities in many cases. There is thus an urgent need to develop new therapeutics, and host defense peptides could be promising candidates. In the Nocardia brasiliensis actinomycetoma mouse model, we demonstrated that the host defense peptide DMS-DA6 was more effective than the classical antibiotic linezolid in decreasing the bacterial load and inflammation in the infected footpad, paving the way for its incorporation in human trials. We thus propose the use of DMS-DA6 as an alternative therapy before amputation of the infected extremity.