Using Bacterial Molecules to Kill Bacteria

Image by Sage Ross [CC-BY-SA 3.0]

By Henry Bryant

The discovery of the first antibiotic — Penicillin — in 1928 was one of the greatest accidents to have happened in the medical field. Being able to treat bacterial infections has saved millions of lives. Now nearly 100 years after the discovery, medicine is faced with a new problem: antibiotic resistance. In the U.S. alone, over 2.8 million people get antibiotic-resistant infections, out of which 35,000 die every year.1 As antibiotics are used more frequently, the chance that antibiotic resistance develops increases. While reducing the overuse of antibiotics can significantly combat resistance, the resistance still has a low potential of occurring during each use. Antibiotic resistance occurs when all bacteria susceptible to an antibiotic are killed, leaving only naturally resistant bacteria. The resistant bacteria no longer have to compete for space and resources and therefore grow and multiply rapidly. The potential for antibiotic resistance does not mean that antibiotic use should be stopped to prevent resistance, but rather creates a perpetual need for new antibiotic discoveries. Dr. Bo Li, an associate professor in the chemistry department at UNC-Chapel Hill, investigates three aspects related to antibiotic discovery: natural products, antibiotic modes of action, and virulence factors (Figure 1). Natural products are bioactive molecules that are made by a living organism. Specifically, Dr. Li researches potential antibiotics that are produced naturally by bacteria. His research seeks to understand why bacteria themselves would make antibiotics.Although seemingly counterintuitive, antibiotics are quite effective in helping bacteria both survive and thrive Dr. Bo Li, PhD. in complex environments. Bacteria make antibiotics naturally to compete with other types of bacteria for the limited resources, and the bacteria have developed protections against the antibiotics they produce so that they are unharmed. Within the study of natural product antibiotics, the Li Lab has two main objectives: to find out which natural products could potentially be used as antibiotics, then discover how the bacteria make these natural product molecules. The most common way to test a molecule for antibiotic properties is by testing its potential to prevent bacterial growth and then, measuring the minimum concentration of the molecule needed to prevent growth. Once a molecule has been identified as an antibiotic, the Li Lab uses a va-

Carolina Scientific physical science riety of advanced biochemical methods to determine the molecules even more difficult. For example, Dr. Li how the molecule is produced. By discovering how discovered an antibiotic, holomycin, which disrupts the antibiotics are made, scientists can then refine the use of metal ions in the cell (Figure 2). While the process to increase efficiency add to the overall such uncommon novel modes of action are more difunderstanding of bacteria and natural production ficult to explore, their specificity gives the antibiotics mechanisms. the potential to overcome bacterial resistance to exOnce an antibiotic has been identified, the next isting antibiotics. The information on mode of action goal of the Li Lab is to investigate how the antibiotic is an important step to move antibiotics toward cliniworks to eliminate bacteria, called the “mode of ac- cal use in humans and animals. The final objective of Dr. Li and her lab is one that she has “on [her] mind a lot.”3 Her goal is to look at virulence factors, small molecules made by infectious bacteria, which can enable the bacteria to cause infections. Virulence factors are the most unexplored of the three subject areas in Dr. Li’s lab, yet they are crucial in understanding how bacteria infect and

Figure 1. Mode of action for the antibiotic Holomycin, avoid the host’s defenses. Small-molecule virulence which was discovered in Dr. Li’s lab. factors also have the potential to one day be targeted in the treatment of bacterial infections. However, at tion.” There are five main ways that common antibiot- this point, not enough is known to develop any cliniics kill bacteria. The first is by disrupting the replication cal treatments. of DNA — the genetic material of all organisms — so Outside of her scientific research goals, Dr. Li that bacteria cannot divide and multiply. The second trains a variety of science students at UNC for them method is when antibiotics disrupt the production to become “fearless problem-solvers.”3 She takes of proteins — the molecules that perform nearly all great joy in walking through the lab to interact with functions in a cell — so that the bacteria can no lon- her students, regularly meeting with them to discuss ger function. The third method is by inhibiting the their research, help them overcome any hurdles, and transcription of DNA into RNA. RNA is an intermediate contribute her own vision. Dr. Li is very proud of her that converts the genetic information from DNA into research and says it feels “invigorating” to share it functional proteins. The fourth and fifth ways operate with others — to be able to add a grain of sand to the by disrupting the cell wall or membrane of bacteria. beach of knowledge. Both structures protect the cell and serve as gates to keep cell contents in and foreign material out. When References 1. Biggest Threats and Data. 18 Jun. 2020, https://www.cdc. either the cell membrane or cell wall are damaged, gov/DrugResistance/Biggest-Threats.html. Accessed 17 Sep. these gates can no longer perform their function and 2020. the cell will then die.2 Determining if an antibiotic op- 2. Nonejuie, P.; Burkart, M., Pogliano, K., & Pogliano, J. erates via one of five methods is the initial step in dis- Proceedings of the National Academy of Sciences, 2013. covering how it works. Dr. Li is researching antibiotics Bacterial cytological profiling rapidly identifies the cellular pathways targeted by antibacterial molecules, 110(40), 16169-that have novel modes of action that do not fall into 16174. doi:10.1073/pnas.1311066110 the five common categories which makes studying 3. Interview with Bo Li, Ph.D. 09/15/20.

Figure 2. Illustration of the flow of discovery of virulence factors from genome to bacterial impact.