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.
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.
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.
Wayne, L. G. & Hayes, L. G. 1996.
An in vitro model for sequential study of down shift of
Mycobacterium tuberculosis through two stages
of non-replicating persistence. Infection and Immunity 64, 2062-9.
Stover, C.K., et al. 2000.
A small-molecule nitroimidazopyran drug candidate for the
treatment of tuberculosis.