Format

Send to

Choose Destination
PLoS Pathog. 2018 Apr 26;14(4):e1006974. doi: 10.1371/journal.ppat.1006974. eCollection 2018 Apr.

Matrix metalloproteinase inhibitors enhance the efficacy of frontline drugs against Mycobacterium tuberculosis.

Author information

1
Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY, United States of America.
2
Public Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, United States of America.
3
School of Electrical and Computer Engineering, Cornell University, Ithaca, NY, United States of America.
4
Department of Biomedical Engineering, Duke University, Durham, NC, United States of America.
5
Department of Microbiology and Immunology, Cornell University, Ithaca, NY, United States of America.
6
Department of Biomedical Sciences and Cornell Stem Cell Program, Cornell University, Ithaca, NY, United States of America.
7
Key Laboratory of RNA Biology, Key Laboratory of Protein and Peptide Pharmaceutical, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.

Abstract

Mycobacterium tuberculosis (Mtb) remains a grave threat to world health with emerging drug resistant strains. One prominent feature of Mtb infection is the extensive reprogramming of host tissue at the site of infection. Here we report that inhibition of matrix metalloproteinase (MMP) activity by a panel of small molecule inhibitors enhances the in vivo potency of the frontline TB drugs isoniazid (INH) and rifampicin (RIF). Inhibition of MMP activity leads to an increase in pericyte-covered blood vessel numbers and appears to stabilize the integrity of the infected lung tissue. In treated mice, we observe an increased delivery and/or retention of frontline TB drugs in the infected lungs, resulting in enhanced drug efficacy. These findings indicate that targeting Mtb-induced host tissue remodeling can increase therapeutic efficacy and could enhance the effectiveness of current drug regimens.

PMID:
29698476
PMCID:
PMC5919409
DOI:
10.1371/journal.ppat.1006974
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Public Library of Science Icon for PubMed Central
Loading ...
Support Center