A Clofazimine-Containing Regimen Confers Improved Treatment Outcomes in Macrophages and in a Murine Model of Chronic Progressive Pulmonary Infection Caused by the Mycobacterium avium Complex

Ju Mi Lee, Jiyun Park, Sangwon Choi, Byung Woo Jhun, Su Young Kim, Kyung Wook Jo, Jung Joo Hong, Lee Han Kim, Sung Jae Shin

Research output: Contribution to journalArticlepeer-review

Abstract

Treatment outcomes using the standard regimen (a macrolide, ethambutol, and rifampicin) for Mycobacterium avium complex-pulmonary disease (MAC-PD) remain unsatisfactory. Thus, improved treatment regimens for MAC-PD are required. Clofazimine has recently been revisited as an effective drug against mycobacterial infection. We performed a comparison between the standard regimen and an alternative regimen (replacing the rifampicin of the standard regimen with clofazimine) based on the intracellular anti-MAC activities of the individual drugs in a murine model of chronic progressive MAC-pulmonary infection (MAC-PI). The intracellular anti-MAC activities of the individual drugs and their combinations in murine bone marrow-derived macrophages (BMDMs) were determined. The treatment efficacies of the standard and clofazimine-containing regimens were evaluated in mice chronically infected with M. avium by initiating 2- and 4-week treatment at 8 weeks post-infection. Bacterial loads in the lung, spleen, and liver were assessed along with lung inflammation. Insufficient intracellular anti-MAC activity of rifampicin in BMDMs was recorded despite its low in vitro minimum inhibitory concentrations (MICs), whereas optimal intracellular killing activity against all tested MAC strains was achieved with clofazimine. Compared to the standard regimen, the clofazimine-containing regimen significantly reduced CFUs in all organs and achieved marked reductions in lung inflammation. The replacement of rifampicin with clofazimine in the treatment regimen resulted in more favorable outcomes in an animal model of chronic progressive MAC-PI. Intriguingly, 2 weeks of treatment with the clofazimine-containing regimen reduced bacterial loads more effectively than 4 weeks of treatment with the standard regimen in M. avium-infected mice. Thus, the clofazimine-containing regimen also had a treatment-shortening effect.

Original languageEnglish
Article number626216
JournalFrontiers in Microbiology
Volume11
DOIs
Publication statusPublished - 2021 Jan 14

Bibliographical note

Funding Information:
This work was supported by the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health and Welfare, Republic of Korea (HI20C0017 to SS and BJ) and the Korea Research Institute of Bioscience and Biotechnology Research Initiative Program, Republic of Korea (KGM4572013 to SS and JH).

Funding Information:
We would like our sincere gratitude to Dr. Won-Jung Koh for his contribution to initiate, conceive, and design this work. He was our mentor and project leader of our team. Funding. This work was supported by the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health and Welfare, Republic of Korea (HI20C0017 to SS and BJ) and the Korea Research Institute of Bioscience and Biotechnology Research Initiative Program, Republic of Korea (KGM4572013 to SS and JH).

Publisher Copyright:
© Copyright © 2021 Lee, Park, Choi, Jhun, Kim, Jo, Hong, Kim and Shin.

All Science Journal Classification (ASJC) codes

  • Microbiology
  • Microbiology (medical)

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