De-centering the drug: Violet light and amphotericin B enhance antileishmanial activity through additive and host-directed effects.

Cutaneous leishmaniasis (CL) is a neglected tropical disease associated with significant toxicity of current treatments, high costs, and emerging parasite resistance, highlighting the need for alternative therapeutic strategies. In this context, integrated light-drug approaches have emerged as a promising avenue to improve efficacy while reducing drug burden. This study evaluated the combined effects of violet LED phototherapy (400 ± 10 nm) and Amphotericin B (AmB) against promastigotes of Leishmania amazonensis, L. braziliensis, and L. major, as well as in RAW 264.7 macrophages infected with L. amazonensis amastigotes. The combination significantly reduced parasite viability compared to monotherapies, with the most pronounced effects observed at higher light fluence (9.0 J cm-2). In infected macrophages, the combined treatment reduced infection rates and enhanced nitric oxide (NO) production, suggesting activation of host antimicrobial mechanisms. To quantitatively assess the interaction between treatments, a Bliss independence analysis was performed. The results demonstrated that the interaction profile is predominantly additive, with context-dependent enhancements under specific experimental conditions, rather than consistently synergistic effects. Overall, these findings indicate that violet light and low-dose AmB can jointly improve antiparasitic outcomes while modulating host-pathogen interactions. This approach represents a promising, accessible, and potentially less toxic strategy for CL treatment, supporting further investigation in in vivo models.