[Fe(phen) _<b>3</b> ] ^<b>2+</b> and [Fe(phen) _<b>3</b> ] ^<b>2+</b> -Loaded Nanostructured Lipid System: <i>In Silico, In Vitro,</i> and <i>In Vivo</i> Efficacy against <i>Mycobacterium tuberculosis</

Tuberculosis (TB), caused by <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>), 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 <i>Mtb</i> cell wall, suggesting that FEP interferes with its synthesis. <i>In silico</i> analyses and whole-genome sequencing (WGS) supported these findings, identifying mutations in key genes, such as <i>ponA1</i>, which encodes a penicillin-binding protein involved in peptidoglycan synthesis. <i>In silico</i> 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 <i>Mtb</i> H37Rv, free FEP and NLS@FEP achieved complete elimination of pulmonary infection.