**6. Clinical implications**

**Figure 3.** Induction of lipid droplet biogenesis in macrophages by *Mycobacterium tuberculosis*. 1) Recognition of bac‐ teria by Toll-like receptors (TLR) trigger phagocytosis and subsequent formation of lipid droplets. 2) The infected mac‐ rophage produces reactive oxygen species (ROS), which oxidize LDL. 3) The binding of OxLDL to type 1 scavenger receptors CD36 and LOX1 induces increased surface expression of both receptors and increases uptake of host´s oxi‐ dized fatty acids. 4) Mycobacterium-laden phagosomes internalize lipid droplets. 5) Within the lipid droplets the bac‐

**Figure 4.** Basic mechanisms of lipid droplet induction in *M. leprae* infected macrophages. *M. leprae* attaches to TLR2 and TLR6. Heterodimerization of TLR2 and TLR6 induces downstream signalling and subsequent accumulation by LD formation. [102,105]. In SCs TLR6, but not TLR2, is essential for *M. leprae*-induced LD biogenesis [101]. Cholesterol from the LDs accumulates at the site of mycobacterial entry and promotes mycobacterial uptake. Cholesterol also re‐ cruits TACO from the plasma membrane to the phagosome [61]. TACO prevents phagosome-lysosome fusion and pro‐ motes intracellular survival [62,63]. Hypothetical uptake of oxidized lipids by scavenger receptors in *M. leprae*: Reactive oxygen species might oxidize low-density lipoprotein (LDL) to oxLDL, which is thought to be subsequently bound and taken up by scavenger receptors CD36 and LOX1. CHO, cholesterol. Unknown mechanisms for LD induc‐

Mycolic acids and oxygenated mycolic acids are strong inducers of monocyte-derived macrophages differentiation into foamy macrophages [19,106]. Peyron et al. demonstrated

tion are indicated with a question mark.

**5.3. Mycolic acids induce the formation of foamy macrophages**

teria form lipid bodies and finally enter the dormant state. ApoB-100, apolipoprotein B-100.

44 Tuberculosis - Current Issues in Diagnosis and Management

Several enzymes of the mycobacterial lipid-biosynthesis are regarded as targets for new antitubercular compounds. The research focused on enzymes, involved in the biosynthesis of lipid compounds of the mycobacterial cell wall [107]. Especially the biosynthesis of the highly toxic cord factor is an attractive target. The cord factor is synthesized by the antigen 85 complex [108,109]. It was recently shown that one member of the complex, antigen 85A is involved in the formation of intracellular lipid bodies [71]. Antigen 85 is an important virulence factor. It has been shown that *M. tuberculosis* requires the expression of Ag85A for growth in macro‐ phages [110]. *M. tuberculosis* strain lacking Ag85C shows an decrease of 40% in the amount of cell wall linked mycolic acids [111,112]. The treatment by a trehalose analogue, 6-azido-6 deoxy-α,α'-trehalose (ADT) inhibits the activity of all members of Ag85 complex *in vitro* [108, 113]. Also ethambutol targets the synthesis of arabinogalactan, isoniazid and ethionamide inhibit biosynthesis of mycolic acids [107].

The most potent inhibitor for mycolic acid biosynthesis is isoniazid (INH). INH is a prodrug which is converted to the isonicotinoyl radical by KatG. INH forms a covalent adduct with NAD. This INH-NAD adduct inhibits FAS-II enoyl-ACP reductase InhA, which in conse‐ quence leads to inhibition of mycolic acid biosynthesis, and ultimately to cell death [114-117]. The inhibitors of fatty acid biosynthesis are summarized in Figure 2 and Table 2.


**Table 2.** Inhibitors of fatty acid biosynthesis
