There has been a recent surge in the number and severity of cholera cases in certain parts of the world including Haiti, India and South Sudan. In the face of an epidemic, the World Health Organization and its affiliates have mobilized their efforts to distribute efficient treatment and sanitation services to the populations affected by cholera.

The treatment of cholera, like any other bacterial disease, relies on a standard antibiotic therapy accompanied by a steady oral rehydration course for the patients. Cholera — caused by the bacterium Vibrio cholerae — causes severe diarrhea and nausea, and could be potentially fatal as the body gets severely dehydrated. In fact, as many as 142,000 deaths are caused annually as a consequence of cholera.

The disease has long been associated with poverty, with the scientific literature to support the correlation as well. The association arises from the causative agent of the disease: the bacteria causing symptoms of cholera thrives in unsanitary water, which is unfortunately widely used as drinking water in impoverished areas. Once they enter the human body, the bacteria have a very short incubation period, causing them to spread quickly and efficiently. The exceptionally virulent bacteria then release toxins, which cause the symptoms of cholera.

To treat these symptoms, antibiotics are typically administered to the patients in tandem with rehydration salts. The antibiotics that function to kill the bacteria are typically of the tetracycline family. The tetracycline-derived antibiotics, however, have become notorious for their rapid decline in clinical efficacy due to antibiotic resistance.

The mode of action of the tetracycline antibiotics is inhibition of protein biosynthesis in the target bacterium. This is accomplished by blocking the bacterial ribosomes, which are the site for protein synthesis. However, many bacteria, including strains of V. cholerae, have developed antibiotic-resistant genes, which efflux the antibiotics from the cell and render them useless.

This resistance to previously one of the most effective, safe and broad-spectrum antibiotics has spurred research into discovering viable alternatives. One of these alternatives is to manufacture a molecule that inhibits toxin production directly. This approach aims to stop the process of bacterial biosynthesis right where it begins: at genetic transcription.

The process of producing cholera toxin also begins with a transcribed gene, which is then translated to a protein toxin. The current objective is to isolate elements within the bacterial DNA that regulate this process, which are called promoters, as well as inhibitors for the promoter. The inhibitory elements can bind to the promoter which, in turn, would stop the transcription process for the specific gene altogether.

For the inhibition of the cholera toxin-producing gene, a class of molecules labeled toxT transcription inhibitors have been identified. These not only inhibit the process of toxin production but also down-regulate the production of colonization factors. The action of toxT, therefore, can stop the production of disease-causing toxins as well as prevent the bacteria from forming large colonies.

These studies depict a different yet successful possibility of approaching the antibiotic resistance issue. The efficient manufacturing and safety of small molecule inhibitors for mainstream pharmaceuticals remains a challenge for the future; however, the current research results are indicative of a positive outcome.

– Atifah Safi

Sources: United Nations, NIH, American Society for Microbiology, WHO
Photo: Mother Earth Living