CHEMISTRY 2000 Topics of Interest #1: Blowing up Bacteria with Nitrogen Monoxide (NO)

Current Treatments for Tuberculosis Mycobacterium tuberculosis, the bacteria causing tuberculosis (TB), infects one third of the world’s population! Only about 10% of those infected develop symptoms; the other 90% have what is called a latent infection in which immune cells have isolated the bacterial cells by surrounding them. Since latent infections can easily turn into symptomatic infections, it is still important to treat latent infections – particularly since the survival rate for symptomatic infections is only ~50%. TB is treated by using a mixture of antibiotics to kill the bacteria. Due to the slow growing nature of M. tuberculosis, it is necessary for a patient on antibiotics to take them for 6-12 months to fully clear the infection. If they don’t, antibiotic resistance can become a problem – and frequently does. Development of new antibiotics is therefore important. R. Singh, C.E. Barry et al Science (2008) 322, ; summarized in Nature (2008) 456, 548. Image above from CDC.

Current Treatments for Tuberculosis The antibiotics in the anti-TB cocktail operate via different means: Rifampicin interferes with protein synthesis by blocking the DNA->RNA step of the DNA->RNA->protein sequence. Streptomycin also interferes with protein synthesis. Isoniazid and ethambutol interfere with production of essential components of the bacterial cell wall. As a result, they are primarily effective when the bacteria are dividing (and needing to build more cell walls). When a healthy person is infected by tuberculosis, their immune system attempts to contain the infection by engulfing the bacteria in cells which produce NO, a highly reactive radical which is, according to Dr. C.E. Barry, “akin to a bomb blast that kills the bacteria from within”. Unfortunately, the amount of NO produced is often not enough to kill all of the bacteria. R. Singh, C.E. Barry et al Science (2008) 322, ; summarized in Nature (2008) 456, 548. Image above from CDC.

Nitric Oxide and Tuberculosis A new antibiotic, still in the experimental stages, has been found to be capable of killing dormant cells in the same way as the human immune system – by releasing NO. Controlling the dose of the antibiotic would allow control of the amount of NO released. After the drug enters a bacterial cell, an enzyme produced by the bacteria itself breaks down the drug, releasing NO. This targets the NO directly against the bacterial cell and means that the drug should not produce NO if taken up by human cells as they lack the relevant enzyme. R. Singh, C.E. Barry et al Science (2008) 322, ; summarized in Nature (2008) 456, 548. Image above from CDC.

Nitric Oxide and Tuberculosis How does NO kill bacteria? NO has an odd number of electrons. It must therefore have at least one unpaired electron, making it a free radical: Particular targets for the NO free radical are enzymes containing sulfur (very common) and/or iron (recall discussion of CO poisoning in CHEM 1000). It also scavenges any free iron in the cell.