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 Mycolic Acid Biosynthesis

M. tuberculosis has an extremely rigid cell wall containing abundant mycolic acids, which are cell wall lipid components specific to mycobacterial organisms. Such characteristics in the cell envelope are important in the virulence and persistence of MTB, since a strong cell wall structure confers high resistance of the bacteria to macrophage antimicrobial effector molecules that are released into bacteria-engulfing phagocytic vesicles and attack intraphagosomal MTB organisms. Enzymes needed for biosynthesis of mycolic acids, such as methyl transferase (PcaA),[15] ß-ketoacyl-acyl carrier protein synthase (KasAB and FabH),[16,17] acyl-AMP ligase (Fad32)[18] and polyketide synthase (Psk13),[19] are good targets for anti-TB drug development. The three enzymes now described are promising drug targets for new anti-TB agents.

Methyl Transferase

Recently, a novel methyl transferase (PcaA) encoded by the pcaA gene has been identified during screening for mutants with a colonial morphology lacking the superfine cord formation associated with virulence.[15] PcaA synthesizes a single cyclopropane residue on the mycolic acids and, in bacteria, this modification occurs during the transition from active growth to stationary phase.[15] Notably, cyclopropanated mycolic acids are the major component in the cell wall of pathogenic but not saprophytic mycobacteria.[20] Indeed, such modifications of mycolic acids increase the resistance of mycobacteria to the antimicrobial effects of reactive oxygen intermediates (ROIs), one of the major antimicrobial effectors of macrophages.[21] The pcaA mutants replicate normally, but are defective for persistence in mice. Thus, PcaA is thought to serve as a promising drug target for new anti-TB agents.

ß-ketoacyl-acyl Carrier Protein Synthase

Biochemical and structural analyses by Bhatt et al. revealed that the ß-ketoacyl-acyl carrier protein synthase KasB (encoded by the kasB gene)-deficient mutant strain synthesized mycolates with shorter chain lengths.[16] Moreover, KasB deletion caused loss of ketomycolic acid trans-cyclopropanation and a drastic reduction in methoxymycolic acid trans-cyclopropanation associated with the trans-cyclopropane synthase CmaA2,[22] resulting in the alteration of colony morphology and abolishment of cord formation. The most profound effect of KasB deletion was the ability of the mutant strain to persist in infected immunocompetent mice without causing disease or mortality. Thus, KasB is closely related to the virulence of MTB and, therefore, is an attractive drug target for new anti-TB drugs.

Enoyl-acyl Carrier Protein Reductase

Isoniazid (INH) affects cell wall biosynthesis via alterations of the MTB type II fatty acid biosynthesis (FAS-II) pathway, particularly the inhibition of InhA.[23,24,25] InhA continues to be a promising drug target of MTB, even today. In this context, Boyne et al. recently searched for InhA inhibitors, which do not require activation by KatG, among various A-ring-modified diphenyl ether compounds.[26] The most active compounds, 6PP and 8PP, had MICs of approximately 2µg/ml for MTB H37Rv (INH susceptible). These compounds exhibited the same levels of antimicrobial activity against the KatG wild-type strain and KatG point mutated or -deleted mutant strains of clinical MTB isolates.[26] By synthesizing high-affinity InhA inhibitors that did not require KatG activation, both 6PP and 8PP were fully active against MDR-TB clinical isolates. In addition, the in vivo studies of Boyne etal. indicate that 6PP and 8PP exhibit low levels of cytotoxicity and can inhibit intramacrophage MTB organisms, but still have a limited bioavailability.[26] In any case, the development of new potent anti-tuberculous drugs, which are active against INH-resistant MTB, by employing InhA protein as a drug target, is expected.

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