Immunomodulatory agents combat multidrug-resistant tuberculosis by improving antimicrobial immunity.

Background Multidrug-resistant tuberculosis (MDR-TB) has low treatment success rates and new treatment strategies are needed. We explored if treatment with vitamin D (vitD) and phenylbutyrate (PBA) could improve conventional chemotherapy by enhancing immune-mediated eradication of Mycobacterium tuberculosis. Methods A clinically relevant model was used consisting of human macrophages infected with M. tuberculosis-isolates (n=15) with different antibiotic-resistance profiles. The antimicrobial effect of vitD+PBA, was tested together with rifampicin or isoniazid. Methods included colony-forming units (intracellular bacterial growth), mRNA expression analyses (LL-37, β-defensin, nitric oxide synthase, and dual oxidase-2), RNA interference (LL-37-silencing in primary macrophages), western blot and confocal microscopy (LL-37 and LC3 protein expression). Results VitD+PBA inhibited growth of clinical MDR-TB strains in human macrophages and strengthened intracellular growth inhibition of rifampicin and isoniazid via induction of the antimicrobial peptide LL-37 and LC3-dependent autophagy. Gene-silencing of LL-37 expression enhanced MDR-TB growth in vitD+PBA-treated macrophages. The combination of vitD+PBA and isoniazid were equally effective to reduce intracellular MDR-TB growth as compared to a >125-fold higher dose of isoniazid alone, suggesting potent additive effects of vitD+PBA with isoniazid. Conclusions Immunomodulatory agents that trigger multiple immune pathways can strengthen standard MDR-TB treatment and contribute to next-generation individualized treatment options for difficult-to-treat pulmonary TB patients.