Tuberculosis
Tuberculosis is a contagious bacterial disease that primarily involves the lungs, but can occur in other tissues (lymph, CNS, pericardium, liver, etc.). Tuberculosis may develop after inhaling infected droplets sprayed into the air from a cough or sneeze of an infected person. The World Health Organization (WHO) estimates that 1.6 million deaths resulted from TB in 2005, and more than 2 million deaths are expected this year. Both the highest number of deaths and the highest mortality per capita are in the Africa Region. Opportunistic tuberculosis has also become a significant problem in immunocompromised patients. ..
Mycobacteria are Gram-positive, non-motile, pleomorphic rods, related to the Actinomyces. Most Mycobacteria are found in habitats such as water or soil. However, a few are intracellular pathogens of animals and humans. Mycobacterium tuberculosis, along with M. bovis, M. africanum, M. microti, and M. canettii. all cause tuberculosis, and are members of the tuberculosis species complex. Each member of the complex is pathogenic, but M. tuberculosis is pathogenic for humans while M. bovis is usually pathogenic for animals.
M. tuberculosis is an obligate aerobe mycobacterium that divides every 15 to 20 hours. This is extremely slow compared to other bacteria, which tend to have division times measured in minutes. It can withstand weak disinfectants and can survive in a dry state for weeks but can grow only within a host organism. The organism is identified microscopically by its staining characteristics: it retains certain stains after being treated with acidic solution, and is thus classified as an "acid-fast bacillus". Acid-fast bacilli can be visualized by fluorescent microscopy, and by auramine-rhodamine stain. The reason for the acid-fast staining seen in mycobacteria is because of its thick waxy (high lipid content) cell wall.
Image from http://www3.niaid.nih.gov/topics/tuberculosis/WhatIsTB/ScientificIllustrations/
Drug Therapy for TB - First-Line
Agents
Tuberculosis can usually be cured with a combination of first-line drugs taken for several months. The hallmark of tuberculosis therapy is that very long treatment regimens are required (9-18 months) to eradicate the bacteria present in encysted form.
Isoniazid. Isoniazid (INH) acts as a pro-drug, and is activated inside the parasite by a catalase-peroxidase enzyme known as katG. This activation produces highly reactive species I and II, which appear to bind to and inactivate an enzyme called inhA. These species can also react with cellular biomolecules to form the metabolites isonicotinaldehyde, isonicotinic acid and isonicotinamide. The inhA enzyme is an enoyl reductase that is required during cell wall biosynthesis, and thus the bacteria is killed by lysis. Interestingly, strains of M. tuberculosis that lack the katG gene are resistant to isoniazid.
Rifampin, pyrazinamide, ethambutol and streptomycin. Rifampin and the related rifamycins inhibit bacterial DNA-dependent RNA polymerase by binding to the ß-subunit of the enzyme.Pyrazinamide is an isostere of nicotinamide, and inhibits tuberculosis growth by an unknown mechanism that may involve reduction of the local pH to around 5.4, thus disrupting tha plasma membrane. It is also possible that it acts by disrupting energy metabolism. Ethambutol also acts by an unknown mechanism, but apperas to disrupt cell wall biosynthesis. Streptomycin's mechanism of action has not been fully elucidated, but it is known to inhibit bacterial protein synthesis.
Image from http://www3.niaid.nih.gov/topics/tuberculosis/WhatIsTB/ScientificIllustrations/multidrugResistantIllustration.htm
Drug Therapy for TB - Second-Line
Agents
Multidrug-resistant tuberculosis (MDR TB) occurs when a tuberculosis strain becomes resistant to isoniazid and rifampin. To cure MDR TB, healthcare providers must turn to a combination of second-line drugs. Second-line drugs may have more side effects, longer treatment may be required, and/ot the cost may be up to 100 times more than first-line therapy. MDR TB strains can also grow resistant to second-line drugs, further complicating treatment. The structures and proposed mechanisms for these agents appear below. Although not pictured, fluoroquinoline antibiotics have also been used to treat tuberculosis.
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