Isoniazid Laniazid

Structural Formula Ball-and-Stick Model Space-filling Model

^ = Carbon = Hydrogen 1 = Oxygen ^ = Fluorine ^ = Nitrogen

Year of discovery: 1912 (by Hans Meyer and Josef Mally of Germany); Year of introduction 1952 (Bayer, Hoffmann-La Roche, and Squibb independently); Drug category: Antimycobacterial agent; Main uses. For the treatment of tuberculosis as a monotherapy or in combination with other tuberculosis drugs. It is also used to reduce tremors in patients with multiple sclerosis; Other brand names: Nydrazid, Rimifon, Ditubin, Dinacrin, INH; Related drugs: Rifampin (or Rifampicin), Streptomycin, para-aminosalicylic acid.

Tuberculosis, a highly contagious pulmonary infection caused by Mycobacterium tuberculosis, has taken countless human lives for thousands of years. Its effects are evident in the pathological signs of tubercular damage found on the spines of ancient Egyptian mummies. Tuberculosis is responsible currently for almost 2 million human fatalities annually. The early antibiotics, "sulfa" drugs and penicillins, are totally ineffective against tuberculosis. The first clinically useful antituberculosis agent was streptomycin. However, a few years after its introduction, streptromycin-resistant strains emerged. Combination therapy of tuberculosis with streptomycin and para-aminosalicylic acid, a para-aminobenzoic acid mimic that prevents bacterial synthesis of folic acid (see trimethoprim and methotrexate, pages 136 and 46), was only moderately more useful.

In 1951, three companies, Bayer, Roche, and Squibb independently introduced the potent antituberculosis agent isonicotinic acid hydrazide (INH or isoniazid), a compound that had first been prepared in 1912. Isoniazid proved to be specific and highly effective against tuberculosis, was well-tolerated and relatively inexpensive. Despite 50 years of use, combination therapy with isoniazid is still a first-line treatment for tuberculosis.

Following the success of isoniazid, the search for more potent structural analogs began. As a result, ethionamide and pyrazin-amide were discovered, both of which are still in therapeutic use (see structures on the left).

The initial phase of tuberculosis chemotherapy destroys rapidly growing bacteria. The subsequent clearance of semidormant bacteria requires prolonged therapy, usually six months. The drug regimen must be strictly followed to avoid the emergence of resistant strains. Currently, the most widely used combinations of antibiotics against tuberculosis employ isoniazid, rifampin, streptomycin, or ethambutol. Ethambutol is highly successful when applied in combination with isoniazid since the two act on different aspects of cell wall biosynthesis.

Ethambutol

y ch3

Ethambutol y ch3

p-Aminosalicylic Ethionamide Pyrazinamide acid

Many antibiotics have no effect on tuberculosis bacteria because they cannot cross the cell wall. The tubercular lipid bilayer is unusually rigid and impervious to most lipophilic drugs. The mycobacterial cell wall contains three types of covalently bound macromolecules: (1) peptidoglycans, polymers of peptides and carbohydrates; (2) arabinogalactan, a polymeric carbohydrate, and (3) mycolic acids, very waxy solids. Mycollc acids are high molecular weight fatty acids that are found either in the form of esters with arabinose or as free lipids. An a-mycolate, the most abundant type of mycolic acid, is shown below.

a-Mycolic acid

The mechanism of action of isoniazid appears to involve an NADH-dependent reductase enzyme which plays a role in the synthesis of the mycolic acids.1

KatG

,nh2

Isoniazid nh2

2 reduction

Isonicotinoyl radical o—p—o-p-o nh2

ho oh ho oh

InhA inhibitor

Isoniazid undergoes oxidation once inside Mycobacterium tuberculosis by the catalase-peroxidase enzyme KatG to afford the isonicotinoyl radical, which in the presence of the NADH-dependent reductase enzyme and its cofactor NADH (or NAD1") leads to the deactivation of the reductase enzyme. Specifically, reaction of the isonicotinoyl radical with NAD* gives rise to a compound (shown above) that serves as the inhibitor of the NADH-dependent reductase enzyme.

The X-ray crystal structure of the NADH-dependent reductase enzyme-inhibitor comp lex has been determined. The image below shows the contacts between the inhibitor and the enzyme. The isonicotinoyl moiety is embedded in a hydrophobic pocket, flanked by hydrophobic residues (amino acids Phe149, Gly 192, Tyr158, and Trp22 are shown in green). A mutation of the amino acid Ser94 (shown in cyan) to Ala has been linked to isoniazid resistance.

HYDROPHOBIC POCKET

The eradication of tuberculosis has proved elusive for reasons other than the emergence of resistant strains.3 The organism M. tuberculosis is able to assume a latent or dormant state in which susceptibility to antibiotics is minimal.'1 In addition, the microorganism is able to evade the immune response, either because of its ability to take up residence in sites that cannot be reached by immune cells or because it can assume a non-immunogenic form. Although rifampin and pyrazinamide have strongly cidal effects on M, tuberculosis, the current best treatment with six-month combination therapy using isoniazid, rifampin, pyrazinamide, and etham-butol only has a success rate of 90% in achieving patient sterilization. It has also been a challenge to develop methodology for the screening of new substances to determine their effectiveness against latent M. tuberculosis and their efficiency in achieving sterilization in humans. Nonetheless, because of the obvious need for more antitubercular drugs, there are currently at least five new entities in development that target different biochemical mechanisms.

In principle, effective prevention of tuberculosis should be possible using vaccines. Currently, at least one new vaccine is in clinical trials. However, it is too early to tell whether this approach will be successful within the next decade.

1. Mot. Microbiol. 2006, 62, 1220-1227; 2. Science 1998, 279, 98-102 (1ZID); 3. Exp. Rev. Anli-lnfect. Ther. 2006, 4, 759-766; 4. Nat. Rev Microbiol. 2007, 5. 39-47; Refs. p. 176

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