Integrated platform for linezolid combinations against rifampicin-resistant Mycobacterium tuberculosis: synergy, macrophage apoptosis, and immune modulation
Abstract
To establish an integrated in vitro evaluation platform for identifying effective antibiotic combinations against rifampicin-resistant Mycobacterium tuberculosis (RR-TB), by simultaneously assessing synergistic drug interactions, intracellular bactericidal activity, macrophage apoptosis, and cytokine responses. Using this platform, we investigated the combinatory potential of linezolid (LZD) with five second-line antitubercular agents. The minimum inhibitory concentrations (MICs) of LZD and five second-line drugs were determined using the Alamar Blue microplate assay. Drug–drug interactions between LZD and cycloserine (CS), clofazimine (CFZ), bedaquiline (BDQ), moxifloxacin (MFX), or levofloxacin (LFX) were evaluated using checkerboard microdilution analysis. Drug pairs demonstrating in vitro synergy were further examined in a macrophage infection model. Intracellular bacterial burden was quantified by colony-forming unit (CFU) enumeration. Macrophage apoptosis was assessed using flow cytometry, and cytokine production (IL-12/23 p40, TNF-α, IL-6, and IL-10) was analyzed to characterize immune modulation. LZD demonstrated synergistic interactions with CS and CFZ, whereas no synergy was observed with BDQ, MFX, or LFX. The synergistic combinations LZD + CS and LZD + CFZ significantly reduced intracellular CFU counts, enhanced macrophage apoptosis, and altered cytokine responses, characterized by increased TNF-α and decreased IL-10 levels in infected macrophages. This study…
Read the paper
Related studies
- Synthesis, In Vitro and In Silico Molecular Docking Studies of Novel Phthalimide–Pyrimidine Hybrid Analogues to Thalidomide as Potent Antitubercular Agents
- Exploring the inhibitory performance of expired moxifloxacin and norfloxacin on copper corrosion in saline environment
- Molecular investigation of antimicrobial peptides against Helicobacter pylori proteins using a peptide-protein docking approach
- Screening of novel narrow-spectrum benzofuroxan derivatives for the treatment of multidrug-resistant tuberculosis through in silico, in vitro, and in vivo approaches
- Synthesis, Characterization, Anticancer, Antioxidant, and In Silico Evaluation of Semicarbazides and Thiosemicarbazides
- Fast and accurate prediction of drug induced proarrhythmic risk with sex specific cardiac emulators
Go deeper in Evidence Hub
Evidence Hub adds a study data sheet (design, sample size, evidence level, key numbers), an AI summary and a chat grounded in the paper's text.