Tanshinones target drug-resistant tuberculosis: efficacy, selectivity, and potential mechanism of action

This study evaluates the antimycobacterial potential of tanshinone I (TI), tanshinone IIA (TIIA), and cryptotanshinone (CPT), natural compounds isolated from <i>Salvia miltiorrhiza</i>, against <i>Mycobacterium tuberculosis</i>, the primary etiological agent of tuberculosis. Given the global challenge posed by antimicrobial resistance and the complexity of current treatment regimens, we aimed to identify effective and safe alternative therapies. The compounds' <i>in vitro</i> activity was initially assessed <i>via</i> minimum inhibitory concentration (MIC₉₀) and cytotoxicity index (CI₅₀) determinations, yielding MIC₉₀ values of 1.03, 0.38, and 1.21 μg mL^-1 for TI, TIIA, and CPT, respectively, with low toxicity and high selectivity indices. A narrow antimicrobial spectrum was observed upon testing against representative bacteria, fungi, and non-tuberculous mycobacteria (NTM). Combination assays with rifampicin revealed synergism for TI and indifference for TIIA and CPT, as determined by the fractional inhibitory concentration index (FICI). Scanning electron microscopy (SEM) revealed morphological alterations in the bacilli's cell wall, suggesting it as a possible target of the compounds' mechanism of action. Whole genome sequencing (WGS) of resistant strains identified mutations predominantly in PE_PGRS family genes, supporting the hypothesis that tanshinones modulate cell wall structure. Finally, efficacy was confirmed against multidrug-resistant clinical isolates, with MIC₉₀ values near 1 μg mL^-1. These findings position TI, TIIA, and CPT as promising candidates for developing new therapies against drug-resistant tuberculosis.