Abstract
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.