A new study has uncovered genes within bacteria designed to resist tetracyclines. But the identification of these genes was not the scary part. Researchers confirmed that those genes could destroy all tetracyclines.
The discovery of antibiotic resistance genes against tetracyclines was led by researchers at the National Institutes of Health (NIH) and Washington University in St. Louis (WUSTL), a private research university in the US. Their findings showed the tetracycline-destructase genes in soil bacteria and in some people. These genes could efficiently remove the lethal effects of all tetracycline antibiotics. However, the chemical compound researchers formulated worked against the resistance genes that restored tetracycline efficacy. The results were published in the journal Communications Biology.
The Global Threat of Antimicrobial Resistance
According to the World Health Organization (WHO), a specialized agency of the United Nations, antimicrobial resistance is the ability of a microbe to counter the active ingredients of antimicrobial drugs. This resistance can be exhibited by bacteria, fungi, viruses, and parasites. Microorganisms with resistance to multiple classes of antimicrobials are called superbugs, which can threaten human lives. Without an effective way to kill them, superbugs can easily spike cases of mortality in an outbreak. And if a superbug is highly contagious, the problem may quickly turn into a pandemic.
In bacteria, the resistance is often called antibiotic resistance. Many bacterial strains have evolved to resist different antibiotic classes. While biomedical scientists are aware of this, they did not expect the speed of evolution. When people start abusing and misusing antibiotics, they unnecessarily expose bacteria in their body to the active ingredients. Any surviving bacteria develops a level of resistance. Once they begin multiplying, that resistance may grow stronger in the next-generation bacteria.
According to the WHO Report on Surveillance of Antibiotic Consumption 2016-2018 Early Implementation, 65 countries were confirmed to consume systemic antibiotics in 2015. Because of that, the WHO started monitoring the consumption in 57 low- and middle-income nations in the following year. The overall consumption of antibiotics was between 4.4 and 64.4 defined daily dose (DDD) per 1,000 people per day. Most countries reported that amoxicillin and combined amoxicillin and clavulanic acid were the antibiotics consumed most often, while reserved antibiotics or medications for specific indications only accounted for fewer than 2% of the total antibiotic consumption.
Meanwhile, the US Centers for Disease Control and Prevention (CDC), a federal agency, found that cases of antibiotic resistance in the US remained high in 2017. In the 2019 Antibiotic Resistance Threats Report, the CDC revealed the 315% increase in erythromycin-resistant invasive group A strep, 124% increase in drug-resistant Neisseria gonorrhoeae, and 50% increase in ESBL-producing Enterobacteriaceae cases. Yet, there was a 41% decrease in vancomycin-resistant Enterococcus, a 33% decrease in carbapenem-resistant Acinetobacter, a 29% decrease in multidrug-resistant Pseudomonas aeruginosa, and a 25% decrease in drug-resistant Candida cases.
Genes That Could Incapacitate Tetracyclines Identified
Among many early antibiotics, tetracyclines have been used as first-line medications to treat numerous bacterial infections. Since the 1940s, tetracyclines have saved hundreds of thousands of lives worldwide from crippling infective bacterial strains. Unfortunately, these antibiotics are limited by resistance. As such, doctors carefully prescribe tetracycline to patients with confirmed bacterial infections. Some illnesses tetracycline can treat include bacterial pneumonia, skin and urinary tract infections, and stomach ulcers.
Recently, a study led by the NIH and WUSTL unveiled the emergence of tetracycline resistance genes in human populations. It was initially detected in the wild in soil bacteria. But the initial detection prompted researchers to seek it out in communities. To their surprise, the genes started to spread in people, which could lead to major issues, especially in the time of the COVID-19 pandemic.
"We first found tetracycline-destroying genes five years ago in harmless environmental bacteria, and we said at the time that there was a risk the genes could get into bacteria that cause disease, leading to infections that would be very difficult to treat," explained Dr. Gautam Dantas, a senior author of the study and professor of pathology, immunology, and molecular microbiology at WUSTL.
In 2015, Dr. Dantas discovered 10 various genes that gave bacteria the ability to cut the efficacy of tetracyclines. Due to their main function, researchers dubbed the genes as tetracycline destructases. At the time, researchers had no idea if the genes were widespread or not. So, they sought help from others and expanded their research to find where the genes might be present. A total of 53 soil samples, 176 human stool samples, two animal fecal samples, and 13 latrine samples were screened for the genes.
The screenings yielded 69 extra possible genes with the same capability: cut the tetracycline toxicity. With more data to use, researchers initiated multiple lab experiments to understand these genes better. First, they cloned some of the genes in E. coli bacteria that exhibited no resistance to tetracycline. Next, they tested the modified E. coli to know if it survived exposed to the antibiotic. Results showed that E. coli modified with the destructase genes from soil bacteria inactivated some generations of tetracycline, while E. coli modified with the genes from bacteria related to people destroyed 11 tetracyclines, all of the established types of tetracycline.
Although the results from the modified E. coli were shocking, the real frightening part was the Tet(X7) tetracycline destructase. It was identified as connected to an older destructase in soil bacteria. Researchers theorized that it might be an evolved version of an ancestral source, but with two critical advantages and no tradeoff. They said that the evolution of resistance genes normally deals with an exchange: either its broadness or efficiency. Tet(X7) was observed with both benefits that could be deadly if other pathogenic bacteria would get it.
After the lab experiments, researchers screened for genetic sequences to find the destructase genes in clinical settings. Their screening highlighted a man in Pakistan who was sent to intensive care in 2016 due to a lung infection. The bacterium isolated from the patient carried the Tet(X7) destructase gene. Then, they investigated how exactly the gene works. The gene was found to be similar to other known structures except it was more active.
At the end of the study, a previously designed chemical compound was used to mitigate the destructase genes. So far, the test of the compound in the bacterium from the Pakistan patient worked well in preserving tetracycline toxicity.
Antibiotic-resistant bacteria fight off antibacterial effects by either ejecting the active ingredients or by strengthening weak points. But the new destructase genes directly inactivate the toxic effects of antibiotics. If the genes go freely in human populations, these will breed even scarier superbugs.