Fernanda Manaia Demarqui, Christian Shleider Carnero Canales, Rachel Temperani Amaral Machado, Rafael Miguel Sábio, Ingrid Gracielle M. Silva, Karine B. Barros-Cordeiro, Sônia N. Báo, Masanori Asai, Sandra M. Newton, Paul R. Langford, Fernando Rogério Pavan
High Resolution Image Download MS PowerPoint Slide Tuberculosis (TB), caused by Mycobacterium tuberculosis ( Mtb ), remains one of the leading causes of mortality from infectious diseases worldwide. So, this study investigates the antimicrobial potential of [Fe(phen) 3 ] 2+ (FEP) and FEP-loaded nanostructured lipid systems (NLS@FEP) as an innovative therapeutic approach for TB. The FEP showed promising antimycobacterial activity in simulated physiological environments, with minimum inhibitory concentrations (MIC 90 ) from 3.92 to 0.98 μg mL –1 . FEP combination with rifampicin or pretomanid significantly reduced the MIC 90, with fractional inhibitory concentration index (FICI) of 0.27 and 0.103, respectively. Field emission scanning electron microscopy (FE-SEM) analysis revealed significant structural alterations in the Mtb cell wall, suggesting that FEP interferes with its synthesis. In silico analyses and whole-genome sequencing (WGS) supported these findings, identifying mutations in key genes, such as ponA1, which encodes a penicillin-binding protein involved in peptidoglycan synthesis. In silico modeling predicted high FEP affinity for PonA1, in line with FE-SEM observations; however, these predictions are hypothesis-generating and require functional validation. FEP-loaded nanostructured lipid system (NLS@FEP) was designed to optimize FEP activity, which improved its stability and bioavailability. In a murine model infected with Mtb H37Rv, free FEP and NLS@FEP achieved complete elimination of pulmonary infection.