A Blast to the Past: The Use of Plant-Based Compounds in Fighting Against Antibiotic Resistance

 Advances in the pharmaceutical field across the globe have significantly reduced the fatal impact of bacterial infections inflicted upon humanity. Until the discovery of penicillin - the world’s first antibiotic - by Alexander Fleming in 1928, 43% of deaths were attributed to bacterial infection, including tuberculosis, pneumonia, and malaria. Since then, scientists have conducted further research into the properties of penicillin, applying its chemical properties to develop common antibiotics today, such as amoxicillin, cephalexin, and more. 

Despite the ever-decreasing death rate caused by bacterial infections and the growing presence of antibiotics in our world today, bacteria have found a way to fight back: by developing antibiotic resistance. What was once regarded as a major breakthrough in the science community, penicillin has been rendered obsolete due to growing resistance. Even vancomycin, which is considered a “last ditch resort” for antibiotics, possesses strains of bacteria that have grown resistant to it, such as vancomycin-resistant Enterococcus. It is projected that by the year 2050, 10 million deaths will be attributed to antimicrobial resistance (AMR). How has the potency of antibiotics decreased over time? What mechanisms of action do these resistant strains of bacteria display? And most importantly, what solutions can be implemented to curb the growth of AMR within the world today?

To better understand how antibiotic resistance is developed, we can organize its causes into two categories: internal and external. For its internal causes, it is crucial to understand the functions of antibiotics and the mechanisms of action of the bacteria themselves. For its external causes, we must uncover the practices that misuse and abuse antibiotics in different sectors of our world.

To provide an example of the internal causes of antibiotic resistance within bacteria, we can delve into the history of the discovery of the first antibiotic. In 1928, Alexander Fleming was sorting through his S. aureus-containing Petri dishes when he noticed an unusual growth of mold on one plate. Upon taking a closer look, the zone around the mold appeared clear, as if the mold was excreting a substance that inhibited the growth of bacteria. Through further research and examination, this “mold” was later developed into the commonly known penicillin, capable of eliminating the growth of multiple other bacteria such as streptococcus, meningococcus, and diphtheria bacillus. On the molecular level, penicillin eliminates these bacteria due to its beta-lactam structure, which inhibits the cross-linking of peptidoglycan, a crucial polymer consisting of sugars and amino acids utilized in the creation of the bacteria’s cell wall. 

The discovery of penicillin was a miracle, and it took the world by storm during the Second World War. Many pharmaceutical companies, including Merck, Pfizer, and Squibb, began mass-producing penicillin, increasing the production of units from 21 billion in 1943 to 133,239 billion in 1949. Thousands of lives were saved by the treatment of this “wonder drug,” and what once posed a severe health risk to humans was now reduced to a minor inconvenience.

However, the overprescription of penicillin, along with developed mechanisms of action of its targeted bacteria, soon deemed penicillin utterly useless in this ever-changing world. During the 1960s, around 80% of S. aureus strains grew resistance to penicillin, due to the presence of Penicillin-Binding Protein 2a (PB2a), which made it hard for antibiotics possessing the beta-lactam ring to target the cell wall.

Pharmaceutical companies developed better, more advanced antibiotics with similar mechanisms of action to penicillin during the 1950s-1980s, such as amoxicillin, ampicillin, and cephalosporins, but these newly discovered antibiotics could only treat a narrow spectrum of bacteria, making them less profitable for the companies. This dip in profit resulted in the last discovery of novel antibiotics to be brought to the market in 1987, leading to a “discovery void” lasting from then until now. Therefore, not only are existing antibiotics over-prescribed to the overwhelming majority to drive profit, but there is also zero incentive for pharmaceutical companies to continue to develop stronger antibiotics to help patients suffering from antibiotic-resistant bacteria.

Adding on to the external causes, not only are antibiotics overprescribed to patients, but they are also overused as “quality control” in the agricultural industry. Since many of the livestock raised today are raised in filthy conditions, they are extremely susceptible to bacterial infections. To counter these infections, farmers have fed their livestock antibiotics, leading to increased antibiotic resistance spreading from animal to animal to humans. 

As a final note to these external causes, antibiotics have found a way into soil and water systems, leading to a greater increase in antibiotic resistance. Antibiotic factories frequently release wastewater with astonishingly high concentrations of antibiotics, leading to the development of antibiotic resistance within downstream river bacteria. Additionally, as mentioned above, 90% of the antibiotics fed to livestock are excreted and contaminate the environment, serving as a “hot spot” for bacteria to multiply and develop antibiotic resistance.

The threat of AMR is impending and can cause the destruction of humanity as a whole. However, scientists are looking into alternatives for antibiotics to prevent the peril of AMR from crashing down on us. Recent literature has shown that certain plant-based compounds - phytochemicals - possess promising properties capable of inhibiting bacterial growth. A study published in Nature extracted various phytochemicals from Mediterranean-native seaweeds, such as unsaturated sterols, flavonoids, tannins, and coumarins, which showed effective inhibition of both Gram-positive and Gram-negative strains of bacteria. Pomegranate leaf extract also shows promising antibacterial properties, specifically against Escherichia coli (E. coli), due to its ability to inhibit the CTX-M-9 beta-lactamase enzyme, which breaks down the beta-lactam rings present in aforementioned antibiotics like penicillin and amoxicillin. Finally, a review paper published in Frontiers compiled multiple studies focusing on the effect of various phytochemicals on bacterial growth, showing that extracts from lemongrass, aloe, oregano, rosemary, and thyme effectively inhibit methicillin-resistant S. aureus. 

Phytochemicals have long been used in the past to treat illnesses; just take a look at traditional Chinese medicine (TCM). TCM can be traced back to the Yin and Shang dynasties, which were over 3000 years ago, and includes treatments such as acupuncture, herbal medicine, moxibustion, massage, bleeding, and cupping. Currently, there are 11,146 types of plant medicine, which have been shown to inhibit biofilm formation and modify bacterial cell wall permeability, leading to bacterial cell death. Examples range from obscure to well-known plants such as coptis rhizome, fallopia japonica, and ginger, all possessing bioactive compounds like berberine, caffeic acid, and citric acid. Even if we didn’t understand the mechanisms of action of these medicinal plants back then, we do now through the advancement of scientific research and experimentation.

Plant-based compounds can serve as a crucial alternative to antibiotics in the antibiotic crisis, and alleviate the stress humanity is enduring from this age of increasing AMR. This technology has the potential to save thousands of lives, and through extensive research concerning the mechanisms of action of these compounds, phytochemicals can serve as a principal stepping stone for overcoming the threat of AMR.

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