## 2 Host Directed Therapy
### Inhibition of M. tuberculosis Induced Inflammation and Host Cell Death
#### 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, [PERSON] 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 \(\upmu\)g/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]. \begin{table}
\begin{tabular}{c c c c c c} \hline \hline \multicolumn{1}{c}{**HDT Effect**} & **Compound** & **Target or Mode of Action** & **Notes** & **Clinical Trials** (ClinicalTrials\_gov)** & **References** \\ \hline \multirow{6}{*}{Promote phagosome maturation and enhance autophagy} & Rapamycin (sirolimus) & Inhibition of mTOR & Metabolized by CYP3A4 & – & [11, 12, 13, 14] \\ \cline{2-5}  & Everolimus & Inhibition of mTOR, rapamycin analogue & Anti-cancer agent & NCT02968927 & [18, 22, 23] \\ \cline{2-5}  & Metformin & Activates AMPK & Used to treat diabetes & Phase 2 studies planned & \\  & & & & CTR/201801/011176 & [25] \\ \cline{2-5}  & Imatinib & Inhibition of BCR-ABL & & Used to treat leukaemia & NCT03891901 & [35, 36] \\ \cline{2-5}  & Statins & Inhibition of cholesterol biosynthetic pathway & Cholesterol is relevant in _M. tuberculosis_ persistence & NCT03882177 & \\  & & & & NCT03456102 & [37, 40] \\ \hline \multirow{6}{*}{Induce anti-microbial peptides} & & & & & \\  & & & & & \\  & & & & & \\  & & & & & \\  & & & & & \\  & & & & & \\  & & & & & \\  & & & & & \\  & & & & & \\  & & & & & \\  & & & & & \\  & & & & & \\  & & & & & \\  & & & & & \\ \hline \multirow{6}{*}{4-phenylbutyraterate} & Inhibition of histone & & & NCT01580007 & \\  & deacetylase & Promotes autophagy & NCT01698476 & [57, 58, 59] \\ \cline{2-5}  & Beta defensin 2 (HBD-2) & Reduces _M. tuberculosis_ & High costs and poor & – & [60, 61, 62] \\ \cline{1-1} \cline{2-5}  & & multiplication & stability & – & [63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91,