Faculty Editor: Professor Jeffrey DaCosta
Bacteria are unicellular microorganisms that differ from eukaryotic organisms like plants and animals by a characteristic lack of membrane-bound organelles such as the nucleus. Among the first organisms to inhabit Earth, bacteria are present in copious amounts (on the order of 1030 cells) both inside and outside of the human body, and comprise a variety of structures and functions based on genetic information carried in chromosomes and a plasmid.
Bacteria play a vital roles in both industry and human survival. For example, bacterial exposure can help humans build their immune systems to be less susceptible to pathogenic substances, and bacterial flora in the gut play a crucial role in the digestion of food we eat. Bacteria also function in the production of foods such as cheese and yogurt, and have agricultural and biochemical applications, such as bioremediation (Brazier 2017). However, certain strains of bacteria are harmful, and sometimes deadly, to humans. These strains cause well known diseases in humans, such as typhoid, cholera, tuberculosis, pneumonia, and many sexually-transmitted infections.
Antibiotic resistance refers to the ability of bacteria to acquire mutations and transformations in its genetic material such that it is no longer susceptible to antibiotic drug treatments. When bacteria are exposed to a drug designed to kill the susceptible cells, a population of resistant cells survive and reproduce, passing on genetic resistance to their progeny and conferring this property to the entire bacterial population. However, this resistance is especially grave as it confers the ability for a bacteria stay vital in the presence of antibacterial drugs. Thus, the over-prescription of antibiotics is a major health risk because it can result in the evolution of these resistant bacteria “superbug” strains, despite new technology decreasing the risk of death from bacterial infections (Brazier 2017). According to the World Health Organization, “Even if new medicines are developed, without behaviour change, antibiotic resistance will remain a major threat.”
In response to this critical issue, a team of researchers led by Christopher Goss and Pradeep K. Singh have found quite the unconventional approach to bacterial infection treatments in the wake of antibiotic resistance (Goss et al. 2018). The research team turned their focus to bacterial iron metabolism, which is crucial process of nutrient buildup and breakdown that is a survival determinant for bacteria. More specifically, iron is obtained from blood plasma proteins such as transferrins and hemoglobin (Ratledge). Therefore, targeting this key determinant in the life cycle of bacteria seemed to be a promising outlet for treating bacterial infection. The team found that a treatment of metal gallium disrupted iron metabolism, in rodent blood and also led to decreased survival rates when in vitro tests were performed. Additionally, sputum (a mixture of saliva and mucous) samples from both mouse models of airway infection and human cystic fibrosis (CF) patients treated with gallium displayed reduced growth of the bacteria Pseudomonas aeruginosa. Based on these results, the study was extended to include a nonrandom phase I clinical trial on CF patients. Lung improvement in these patients was evidenced by increased forced exhalation volume, an indicator of how much extra air can be forced out after exhalation. Also, both density and percent survival of P. aeruginosa was seen in patients that received the gallium treatment. According to Goss et al., “The magnitude of gallium-associated lung function improvement we identified in the pilot clinical trial is similar to that produced by approved antibiotics in CF.”
The results of the study displayed that gallium, in micromolar concentrations, inhibited P. aeruginosa growth in both ex vivo and in vitro experiments, as well as patients with CF. It was discovered that the metal inhibited key enzymes in the process of iron metabolism, thereby increasing the susceptibility of bacteria to harmful oxidants, ultimately leading to death. Gallium essentially disrupted metabolism upon its substitution for iron when taken up by bacteria by acting as a“Trojan horse” because it has similar chemical properties as iron. Will bacteria evolve resistance to gallium in a similar way that they develop antibiotic resistance? The study also demonstrated that the development of resistance to the gallium substitute was slower than that toward many antibiotic treatments already on the market. This poses a promising outlook for gallium as a viable treatment for patients with pulmonary infections with a decreased risk of bacterial resistance and thus a longer “shelf life” compared to currently available antibiotic drugs. . This exciting study thus illustrates the possibility to target iron metabolism, and potential other nutritional qualities of bacterial pathogens, to attenuate both bacterial infection and resistance.
Brazier, Yvette. “Bacteria: What You Need to Know.” Medical News Today. October 31, 2017. Accessed October 01, 2018. https://www.medicalnewstoday.com/articles/157973.php.
Goss, Christopher H., et al. “Gallium Disrupts Bacterial Iron Metabolism and Has Therapeutic Effects in Mice and Humans with Lung Infections.” Science Translational Medicine. September 26, 2018. Accessed October 01, 2018. http://stm.sciencemag.org/content/10/460/eaat7520.
Ratledge, C., and L. G. Dover. “Iron Metabolism in Pathogenic Bacteria.” Current Neurology and Neuroscience Reports. Accessed October 01, 2018. https://www.ncbi.nlm.nih.gov/pubmed/11018148.