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

PLoS pathogens, Volume: 14, Issue: 4
April 26, 2018
Yitian Xu Y, Lihua Wang L, Matthew D Zimmerman MD, Kai-Yuan Chen KY, Lu Huang L, Dah-Jiun Fu DJ, Firat Kaya F, Nikolai Rakhilin N, Evgeniya V Nazarova EV, Pengcheng Bu P, Veronique Dartois V, David G Russell DG, Xiling Shen X

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.

Courtesy of the U.S. National Library of Medicine