Avaliação da atividade antimicrobiana da desferrioxamina in sílico e in vitro contra Mycobacterium abscessus subsp. massiliense

Abstract

Infections caused by Mycobacterium abscessus subsp. massiliense (Mabs) pose a growing public health threat, particularly for immunocompromised individuals. Consequently, novel therapeutic strategies are urgently needed to combat bacterial resistance and dismantle biofilm structures. Desferrioxamine (DFO), an iron chelator commonly used in the treatment of iron overload, has shown antimicrobial potential due to its ability to limit iron availability, an essential element for microbial survival. This study aimed to evaluate the antimicrobial activity of desferrioxamine in silico and in vitro against Mabs. In silico analyses were performed to predict pharmacological activity (PASS online), oral availability and pharmacokinetics (SwissADME and PROTOX), toxicity (WaytoDrug), and to characterize the molecular interactions of desferrioxamine with specific enzymatic targets. For the in vitro analysis, molecular assays (PCR), antimicrobial activity assessments, and biofilm formation investigations against Mabs were conducted. The results demonstrate that in silico evaluation (PASS Online) predicted a high probability of iron antagonism by DFO (Pa = 0.911), suggesting potential inhibition of bacterial growth. Predictive pharmacokinetic analysis (SwissADME) indicated high plasma protein binding (>90%) and low intestinal absorption of DFO, factors that may restrict its systemic bioavailability. Moderate toxicity was observed, with mutagenic and nephrotoxic effects. Molecular docking revealed promising interactions of DFO with essential Mabs proteins, suggesting an inhibitory effect. In in vitro assays with RAW 264.7 cells, DFO showed no significant cytotoxicity. DFO significantly inhibited nitric oxide production by M. abscessus-infected RAW 264.7 macrophages. The minimum inhibitory concentration results for DFO reinforce its therapeutic potential and warrant further investigation into its antimicrobial activity. DFO demonstrates a dose-dependent effect on cytokine expression regulation; at low concentrations (0.5 x MIC), DFO reduces pro inflammatory cytokines TNF-α, IL-1β and IL-6. Given these findings, it is concluded that DFO has potential as an adjuvant antimicrobial agent against Mycobacterium abscessus subsp. massiliense, particularly due to its ability to sequester iron and compromise bacterial survival.