New Anti-Tuberculosis Drugs

Tuberculosis has the highest mortality worldwide among all single infectious diseases. The interaction between tuberculosis and the AIDS epidemic, and the surge of multidrug-resistant tuberculosis have further compounded the problem. There is no doubt that tuberculosis remains a primary public health threat. However, standard treatments are limited to those drugs developed more than 30 years ago. New antitubercular drugs with better efficacy have yet to be developed.

Latent Infection

The causal agent of tuberculosis, Mycobacterium tuberculosis, may persist despite active chemotherapy. Historically, it is debatable whether tuberculosis can really be cured. Recent research sheds light on this issue. The possible mechanism for latent infection has been theorized. It is perhaps true that tuberculosis treatment would not take such a lengthy period of time if the latent form of infection did not occur. However, before jumping to any conclusion, it should not be forgotten that drug resistance is also a big factor.

Mycobacteria are obligate aerobes. However, it has been known for years that tubercle bacilli may encounter hypoxic conditions as a result of caseous tissue destruction in acute disease or dormancy inside macrophages in latent infection. Furthermore, a link between oxygen depletion and drug resistance has been established (ref. 1). Dormant bacilli are adapted to anaerobiosis and maintain viability for an extended period of time. The micro-environment containing dormant bacilli might change over time and when oxygen becomes available again, the bacilli resume growth. From this line of arguments, drugs that target dormant bacilli could have a profound impact on tuberculosis therapy. Such drugs may shorten the treatment period for acute infection and eradicate bacilli for latent infection.

PA-824

It is discovered that chemical compounds containing a nitroimidazopyran nucleus possess antitubercular activity (ref. 2). After activation by a mechanism dependent on M. tuberculosis F420 cofactor, nitroimidazopyrans inhibit the synthesis of protein and cell wall lipid. Lead compound PA-824 showed potent bactericidal activity against multi-drug resistant M. tuberculosis. In animal experiments, the bactericidal activity of PA-824 was comparable with that of INH (isoniazid), which also inhibits or interferes with Mycobacterial cell wall synthesis and is currently a first-line drug of choice. However, in contrast to current antitubercular drugs, PA-824 exhibited bactericidal activity against both replicating and static M. tuberculosis and is promising for treating both active and latent forms of tuberculosis. PA-824 could kill the germ even before the disease is developed.
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