Mycothiol (MSH) is a low molecular weight thiol that replaces glutathione in actinomycetes (G. L. Newton et al. J. Bacteriol. (1996) 178:1990). In conjunction with MCA, MSH plays a central role in protecting actinomycetes against alkylating agents and other toxins (G. L. Newton, et al. Biochemistry (2000a) 39:10739). Recently a second highly homologous amidase from M. tuberculosis that is involved in the biosynthesis of MSH has been described (G. L. Newton et al. J. Bacteriol. (2000) 24:6958).
Aerobic organisms are subjected to oxidative stress from many sources, including atmospheric oxygen, basal metabolic activities, and, in the case of pathogenic microorganisms, toxic oxidants from the host phagocytic response intended to destroy the bacterial invader. Glutathione (GSH) is the dominant low molecular weight thiol in most eukaryotes and Gram-negative bacteria, and it plays a key role in protection of the cell against oxygen toxicity and electrophilic toxins (R. C. Fahey and A. R. Sundquist (1991) Adv. Enzymol. 64:1-53; Dolphin, et al, (1989) Glutathione: Chemical, Biochemical, and Medical Aspects pp 45-84, John Wiley & Sons, New York). However, actinomycetes, including Streptomyces and Mycobacteria do not make GSH but produce millimolar levels of mycothiol (MSH, AcCys-GlcN-Ins), an unusual conjugate of N-acetylcysteine (AcCys) with 1-D-myo-inosityl-2-amino-2-deoxy-α-D-glucopyranoside (GlcN-Ins) (G. L. Newton, et al. (1996) J. Bacteriol. 178:1990-1995; S. Sakuda, et al., (1994) Biosci. Biotech. Biochem. 58:1347-1348; H. S. C. Spies and D. J. Steenkamp, (1994) Eur. J. Biochem. 224:203-213; G. L. Newton, et al. (1995) Eur. J. Biochem. 230:821-825) (FIG. 1A).
Antibiotic resistance of pathogenic bacteria, including pathogenic actinomycetes, such as M. tuberculosis, is a well-known problem faced by medical practitioners in treatment of bacterial diseases. Mycobacterium tuberculosis, the causative agent of tuberculosis, is a leading pathogenic cause of death worldwide (Zumla, A. et al. Clinical Review: Tuberculosis. Br. Med. J. (1998) 316:1962). The rise of mycobacterial resistance to common antituberculars such as isoniazid and rifampin, along with the high prevalence of tuberculosis and Mycobacterium avium complex in AIDS patients, has led to a renewed interest in the discovery of antimycobacterial agents with new modes of action.
Therefore, there is a further need in the art for a new class of compounds useful for reducing resistance to existing antibiotics in treatment of bacterial infections in humans and in other mammals, such as domestic and farm animals and useful as antibiotics in treatment of bacterial diseases such as tuberculosis.
USPTO Backgrounds
USPTO Backgrounds