Recent Advances in Antituberculous Drug Development and Novel Drug Targets

Haruaki Tomioka, PhD; Yutaka Tatano, PhD; Ko Yasumoto, PhD; Toshiaki Shimizu, PhD

Disclosures

Expert Rev Resp Med. 2008;2(4):455-471. 

In This Article

Drug Targets in Mycobacterial Cell Wall Biosynthesis

Enzymes Participating in the Biosynthesis of Lipoarabinomannan & Phthiocerol Dimycoserosate

A lipid-rich cell wall structure is important in the pathogenesis of MTB organisms. In MTB, the major cell wall-associated components containing lipid moieties are lipoarabinomannan (LAM), the phthiocerol dimycoserosate (PDIM) family of complex lipids and 6,6'-trehalose dimycolate (TDM). LAM, especially mannosylated LAM (man-LAM), is known to suppress IFN-F-mediated activation of macrophages[27] and to scavenge macrophage-derived ROI molecules.[28] However, synthesis and transport of PDIM, a complex lipid noncovalently bound to the MTB cell membrane and directly involved in mycobacterial virulence, are necessary for in vivo replication of MTB organisms in the host lung.[29] Thus, the following bacterial enzymes and membrane transporters that play crucial roles in the biosynthesis of cell wall components by MTB are thought to serve as promising drug targets for new anti-TB therapeutics:

  • Enzymes needed for biosynthesis of mycolic acids, as described previously;

  • Enzymes participating in the biosynthesis of LAM, such as polyprenol monophosphomannose synthase (Ppm1)[30] and mannosyltransferase (PimB, PimF);[31,32]

  • Enzymes playing central roles in the biosynthesis of PDIM, including PDIM transferase (Papa5), PpsA-E, Mas, Fad26 and FadD28;[29,33]

  • Membrane transporter needed for the transport of PDIM through the cell membrane to the cell surface (mmpL7 gene product).[29]

Enzymes Participating in the Biosynthesis of the Mycolic Acid-arabinogalactan-peptidoglycan Complex

An L-rhamnosyl residue plays an essential structural role in the cell wall of MTB, since arabinogalactan, to which mycolic acids are esterified, thereby forming an outer lipid layer, is connected via a linker disaccharide containing a rhamnosyl residue to a muramic acid moiety of the peptidoglycan.[34] Thus, this rhamnosyl residue, which is not found in humans, plays important roles in the binding of a mycolic acid-arabinogalactan conjugate to peptidoglycan, forming the mycolic acid-arabinogalactan-peptidoglycan (mAGP) complex.[34] Since the mAGP complex serves as a rigid barrier against chemical injury and bactericidal substances, the four Rml enzymes encoded by rml genes, including glucose-1-phosphate thymidyltransferase (RmlA), dTDP-glucose dehydratase (RmlB), dTDP-4-dehydrorhamnose 3,5-epimerase (RmlC) and dTDP-4-dehydrorhamnose reductase (RmlD), that form dTDP-rhamnose from dTDP and glucose-1-phosphate, are attractive targets for the development of new TB therapeutics.[35] Indeed, RmlB and RmlC are essential for the growth of mycobacteria.[36] Recently, Kantardjieff et al. reported that RmlC (Rv3465) of MTB is considered to be the most promising drug target in the dTDP-L-rhamnose pathway because it is structurally unique, highly substrate-specific and does not require a cofactor.[37] Ma et al. screened 8000 compounds in terms of their inhibitory activity against these enzymes (RmlB-D), and identified 11 inhibitors active at 10 µM.[35] In these Rml inhibitors, one drug belonging to rhodanine derivatives (named as 5372) (Figure 1A) exhibited modest antimicrobial activity against MTB (MIC=16 µg/ml). This strategy is thus promising for the development of new anti-TB drugs.

Figure 1.

(A) Rml inhibitor 5372, (B) PknG inhibitor AX20017 and (C) AKT1 inhibitor H-89.

Enzymes Participating in the Biosynthesis of Isoprenoids

Isoprenoids play essential roles in the growth of MTB as follows: polyprenyl phosphate acts as a carrier of activated sugar in the biosynthesis of the arabinan portion of arabinogalactan, arabinomannan and LAM, thereby supporting cell wall synthesis [38]. Moreover, menaquinone, an essential component of the electron transport chain of MTB, contains a side chain derived from polyprenyl diphosphate [39]. Thus, isoprenoids and, consequently, a metabolic pathway for isoprenoid biosynthesis, are essential for cell wall biosynthesis and energy production by MTB organisms.

In eubacteria, all bacterial isoprenoids are generated mainly from isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP), which are synthesized via the methylerythritol phosphate (MEP) pathway. In the MEP pathway, several enzymes play roles in generating IPP and DMAPP from pyruvate and glyceraldehyde 3-phosphate. Above all, 4-diphosphocytidyl-2-C-methyl-D-erythritol synthase (IspD) encoded by the Rv3852c gene is essential for the growth of MTB.[40] The preceding enzyme in the MEP pathway, 1-deoxy-D-xylulose 5-phosphate reductoisomerase (IspC), may be a valid drug target in MTB, although it is nonessential for MTB growth.[41] Together, since no ortholog of MTB IspD exists, the IspD protein is a promising drug target for anti-tuberculous drugs.

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