[Fe(phen) 3 ] 2+ and [Fe(phen) 3 ] 2+ -Loaded Nanostructured Lipid System: In Silico, In Vitro, and In Vivo Efficacy against Mycobacterium tuberculosis.

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 (MIC90) from 3.92 to 0.98 μg mL-1. FEP combination with rifampicin or pretomanid significantly reduced the MIC90, 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.