2.4.5. Targeting Matrix Metalloproteinases for Improved Tissue Repair

Imbalanced inflammation eventually results in host tissue destruction, cavitation and dissemination of bacteria. A main driver of these end-stage events are matrix metalloproteinases (MMP) [96]. Once released from activated or necrotic cells, these zinc dependent proteases cleave the extracellular matrix, mostly collagen, and inhibition with small molecules should restrict tissue damage and exacerbation of the disease. Several in vitro and ex vivo studies identified elevated MMP levels in *M. tuberculosis* infected cells or tissue indicating that these enzymes are engaged [96]. In particular, Andrade and colleagues [97] evaluated the interplay between the levels of MMP and heme oxygenase-1 (HO) and discovered that the abundance of these two markers in plasma correlates with different inflammatory profiles and clinical presentations of TB. To date, the only FDA approved MMP inhibitor is doxycycline, an antibiotic with a dual mechanism of action targeting primarily MMP1 and MMP9. The drug suppressed MMP1 and 9 activities in *M. tuberculosis* infected primary human macrophages [98]. In the same study, doxycycline treatment of *M. tuberculosis*-infected guinea pigs led to reduction of the lung bacterial load compared to untreated animals. However, it is important to note that the substance shows a significant growth inhibitory effect on *M. tuberculosis* in broth (MIC 2.5 μg/mL) making it difficult to differentiate between selective host directed and antibacterial effects in these experiments. Experiments with more selective MMP inhibitors such as marimastat (BB-2516), a collagen peptidomimetic broad spectrum MMP inhibitor, showed adjuvant activity in *M. tuberculosis*-infected mice when combined with isoniazid or rifampicin [99]. In contrast to doxycycline, monotherapy with marimastat had no effect on lung bacterial burden [99].


