Inhibition of Protein Synthesis

The rifamycins (rifampin, rifabutin, rifapentine) are bactericidal and inhibit deoxyribonucleic acid (DNA)-dependent ribonucleic acid (RNA) polymerase of mycobacteria (but not mammals). This enzyme is composed of four subunits; rifamycins bind to the β-subunit, which results in blocking the growing RNA chain (Fig. 49-2). Resistance is conferred by single mutations that tend to occur (>95%) in an 81-base pair region of the rpoB gene that codes for the β-subunit. The aminoglycosides streptomycin, kanamycin, and amikacin act by inhibiting protein synthesis and are described in Chapter 47. Capreomycin, a macrocyclic polypeptide antibiotic, has similar activity and toxicities as aminoglycosides.

FIGURE 49–2 Mechanism of rifampin action. The drug binds to the β-subunit of DNA-dependent RNA polymerase and inhibits RNA synthesis. A, Drug is absent. B, Drug is bound to the polymerase and distorts the conformation of the enzyme so that it cannot initiate a new chain.

Inhibition of Cell Wall Synthesis: Isoniazid (INH)

INH is a bactericidal agent that is thought to inhibit mycolic acid synthesis. Mycolic acids are a major constituent of mycobacterial cell walls (along with arabinogalactan and peptidoglycan). The mode of action of INH is complex, and a current model is shown in Figure 49-3. INH is a prodrug that has to be activated by the M. tuberculosis catalase-peroxidase enzyme encoded by the katG gene. Deletions or mutations in this gene may account for 40% to 50% of clinical INH-resistant isolates. Other mechanisms of resistance may include mutations in three other genes. inhA and kasA code for mycolic acid biosynthetic enzymes, and mutations are found in some INH-resistant isolates. ahpC has also been associated with some INH resistance strains, but its role is unclear.

FIGURE 49–3 Mechanism by which isoniazid kills tubercle bacilli. INH enters by passive diffusion and is activated by katG to a range of reactive species or radicals and isonicotinic acid. These attack multiple targets, including mycolic acid synthesis, lipid peroxidation, DNA, and NAD metabolism. Deficient efflux and insufficient antagonism of INH-derived radicals, such as defective antioxidative defense, may underlie the unique susceptibility of M. tuberculosis to INH.

Pyrazinamide (PZA) is active only against M. tuberculosis and M. africanum; it is inactive against M. bovis and nontuberculous mycobacteria. PZA is active at a low pH (e.g., pH 5), is bactericidal, and has excellent sterilizing activity against semidormant bacteria. PZA is thought to enter M. tuberculosis by passive diffusion and is then converted to the active metabolite pyrazinoic acid (POA) by nicotinamidase/pyrazinamidase (PZase). The target of POA may involve fatty acid synthase I and disruption of mycobacterial membranes by acid (Fig. 49-4). Selected mutations in the PZase gene (pncA) are associated with PZA resistance in M. tuberculosis.

FIGURE 49–4 Proposed mechanism of action of pyrazinamide (PZA). PZA is converted to pyrazinoic acid (POA) by the enzyme encoded by pncA. Its ability to kill M. tuberculosis and not other Mycobacteria species may be due to a selective defect in POA efflux in M. tuberculosis. Proposed targets include the mycobacterial fatty acid synthase 1 and disruption of mycobacterial membranes by acidic action.

Modified from Chan ED, Chatterjee D, Iseman MD, et al. Pyrazinamide, ethambutol, ethionamide, and aminoglycosides. In Rom WN, Garay SM, editors: Tuberculosis, 2nd ed, Philadelphia, Lippincott, Williams & Wilkins, 2004.

The mechanism of action of ethambutol is not well understood. It is thought to interfere with mycobacterial cell wall synthesis by inhibiting synthesis of polysaccharides and transfer of mycolic acids to the cell wall. The target is thought to be encoded by a three-gene operon (embC, embA, embB) that produces arabinosyl transferases that mediate polymerization of arabinose into arabinogalactan, particularly embB. Resistance to ethambutol is most common among M. tuberculosis isolates that are also resistant to INH and rifampin (i.e., MDR strains), probably because of mutations in embB. Ethambutol is effective only on actively dividing mycobacteria.

Other Mechanisms

p-Aminosalicylic acid (PAS) acts as a competitive inhibitor of p-aminobenzoic acid in folate synthesis. Because PAS inhibits only this step in M. tuberculosis, and sulfonamides do not generally inhibit mycobacteria, the enzyme in tubercle bacilli is thought to be distinct.

Other agents used in treatment of mycobacterial diseases include the fluoroquinolones (e.g., levofloxacin, moxifloxacin), which have emerged as important second-line drugs used in the treatment of XDR-TB. They are discussed in Chapter 48.

First Line

INH is well absorbed orally and is widely distributed, with peak concentrations achieved in pleural, peritoneal, and synovial fluids. Cerebrospinal fluid (CSF) concentrations are approximately 20% of plasma levels but can increase to 100% with meningeal inflammation. INH is metabolized by a liver N-acetyltransferase, and the rate of acetylation determines its concentration in plasma and its half-life. As discussed in Chapter 2, slow acetylation is inherited as an autosomal recessive trait. The average plasma concentration of drug in rapid acetylators is half of that in slow acetylators. However, there is no evidence that these differences are therapeutically important if INH is administered once daily, because plasma levels are well above inhibitory concentrations.

Rifampin is well absorbed orally and widely distributed, achieving therapeutic concentrations in lung, liver, bile, bone, and urine and entering pleural, peritoneal, and synovial fluids and CSF, tears, and saliva. Its high lipid solubility enhances its entrance into phagocytic cells, where it kills intracellular bacteria. Rifampin is metabolized in the liver to a desacetyl derivative that is biologically active. Unmetabolized drug is excreted in bile and reabsorbed from the gastrointestinal (GI) tract into the enterohepatic circulation; the deacetylated metabolite is poorly reabsorbed with eventual elimination in urine and from the GI tract. Rifampin induces its own metabolism by inducing the expression of cytochrome P450s, resulting in increased biliary excretion with continued therapy. Induction of metabolism results in reduction of the plasma life by 20% to 40% after 7 to 10 days of therapy. Patients with severe liver disease may require dose reduction, but dose adjustment is not necessary in renal failure. Oral bioavailability of rifabutin is less than that of rifampin, and the plasma half-life is approximately 10 times greater. Rifabutin is more lipid soluble than rifampin and is extensively distributed. Rifabutin also induces its own metabolism but has less of an effect on cytochrome P450s. Rifapentine

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