Virus World

A laboratory study unravels ways non-antibiotic drugs can contribute to drug resistance.  The emergence of disease-causing bacteria that are resistant to antibiotics is often attributed to the overuse of antibiotics in people and livestock. But researchers have homed in on another potential driver of resistance: antidepressants. By studying bacteria grown in the laboratory, a team has now tracked how antidepressants can trigger drug resistance. “Even after a few days exposure, bacteria develop drug resistance, not only against one but multiple antibiotics,” says senior author Jianhua Guo, who works at the Australian Centre for Water and Environmental Biotechnology at the University of Queensland in Brisbane. This is both interesting and scary, he says. Globally, antibiotic resistance is a significant public-health threat. An estimated 1.2 million people died as a direct result of it in 20192, and that number is predicted to climb. Early clues Guo became interested in the possible contributions of non-antibiotic drugs to antibiotic resistance in 2014, after work by his lab found more antibiotic-resistance genes circulating in domestic wastewater samples than in samples of wastewater from hospitals, where antibiotic use is higher. Guo’s group and other teams also observed that antidepressants — which are among the most widely prescribed medicines in the world — killed or stunted the growth of certain bacteria. They provoke “an SOS response”, Guo explains, triggering cellular defence mechanisms that, in turn, make the bacteria better able to survive subsequent antibiotic treatment.

In a 2018 paper, the group reported that Escherichia coli became resistant to multiple antibiotics after being exposed to fluoxetine, which is commonly sold as Prozac. The latest study examined 5 other antidepressants and 13 antibiotics from 6 classes of such drugs and investigated how resistance in E. coli developed. In bacteria grown in well-oxygenated laboratory conditions, the antidepressants caused the cells to generate reactive oxygen species: toxic molecules that activated the microbe’s defence mechanisms. Most prominently, this activated the bacteria’s efflux pump systems, a general expulsion system that many bacteria use to eliminate various molecules, including antibiotics. This probably explains how the bacteria could withstand the antibiotics without having specific resistance genes. But exposure of E. coli to antidepressants also led to an increase in the microbe’s mutation rate, and the subsequent selection of various resistance genes. However, in bacteria grown in anaerobic conditions, levels of reactive oxygen species were much lower and antibiotic resistance developed much more slowly. Moreover, at least one antidepressant, sertraline, promoted the transfer of genes between bacterial cells, a process that can speed up the spread of resistance through a population. Such transfer can occur between different types of bacterium, allowing resistance to hop between species — including from harmless bacteria to pathogenic ones.

Growing recognition

Kiran Patil, who studies microbiome–chemical interactions at the University of Cambridge, UK, says that in the past five years there has been a growing appreciation that many non-antibiotic medicines that target human cells can also affect bacteria and contribute to antibiotic resistance. “The strength of the study is the mechanistic details,” says Patil. Lisa Maier, who is based at the University of Tübingen in Germany and studies interactions between drugs and the microbiome, says that to understand how antidepressants can drive antibiotic resistance, researchers need to determine what molecules the drugs are targeting in the bacteria and to assess the effects of the medications on a wider variety of clinically relevant bacterial species. In 2018, Maier and her colleagues surveyed 835 medicines that did not target microbes and found that 24% inhibited the growth of at least one strain of human gut bacteria. Patil and Maier say it is important to gather evidence to assess the real-world impact of antidepressants on resistance, such as whether antidepressants are driving the accumulation of antibiotic-resistant bacteria, particularly disease-causing ones, in people, animals or the environment. Although significant amounts of antidepressants have been found in wastewater, reported levels tend to fall below the concentrations at which Guo’s group saw significant effects in E. coli. But concentrations of some of the antidepressants that had strong effects in this study are expected to be reached in the large intestines of people taking the drugs.

Follow-up studies Maier says that several studies now link antidepressants and other non-antibiotic pharmaceuticals to changes in bacteria, and that preliminary studies have given the “first hints” regarding how such drugs can affect the microbiomes of people taking them. But in healthy humans, E. coli is found mainly in the large intestine, where conditions are anaerobic, meaning that the process described in the paper might not occur at the same rate in people, says Maier. Future studies should use bacterial growing conditions that model sites at which antidepressants might be acting, says Patil. Guo says his lab is now looking at the microbiomes of mice given antidepressants. Early, unpublished data suggest that the drugs can change the animals’ gut microbiota and promote gene transfer. But Guo and Maier caution people against stopping taking antidepressants on the basis of this research. “If you have depression, that needs to be treated in the best possible way. Then, bacteria second,” says Maier. Researchers and pharmaceutical companies need to quantify the contribution of non-antibiotic pharmaceuticals to antibiotic resistance, says Guo. “Non-antibiotic pharmaceuticals are a big concern that we shouldn’t overlook,” he says.

Published in Nature (Jan. 24, 2023):

https://doi.org/10.1038/d41586-023-00186-y 

These simple experiments illustrate how wearing a mask can stop the spreading of germs. In the study petri plates containing media to grow bacteria are exposed to an individual wearing a surgical mask or not. Conditions tested include coughing, sneezing, talking and singing. The results are striking. Masks block the ejection of droplets that contain bacteria. Exposed petri plates appear full of bacterial colonies when exposed to an individual who is not wearing a mask.

Experiments also confirm the effect of social distancing, and demonstrate how the individual does not spread bacteria to plates exposed at a distance of 6 feet away from the source. Although these experiments evaluate bacterial contamination, the droplets that carry these germs can also transport viruses such as SARS-CoV-2. 

The achievement promises to unlock the potential for making new classes of chemicals — for medicine, food production, and manufacturing. Two years ago, scientists in Britain swapped out the DNA of the bacteria Escerichia coli for a genetic coding program that was entirely human-made. At the time, it was the largest and most complex synthetic genome ever created. On Thursday, that same group of researchers at the Medical Research Council Laboratory of Molecular Biology reported in Science that with continued tinkering, they’ve made their artificial life form virtually invincible to viral infection. Other adjustments to the bacteria’s designer genome endowed the bug with the ability to string together non-natural amino acids to produce proteins never before seen inside a living cell. In an accompanying editorial, scientists not involved in the work said the achievement promises to unlock the potential for making all sorts of new classes of chemicals — for medicine, food production, and industrial manufacturing.  “It’s brilliant work,” Tom Ellis, director of the Center for Synthetic Biology at Imperial College London, who was not involved in the new study, told STAT via email. “It shows two really exciting applications that can be achieved by having cells with synthetic genomes that have been genetically recoded.” 

DNA, fundamentally, is an information storage system; your DNA stores all the information required to build the molecules and cells and tissues that make you, you. But to actually build those things, you also need a storage-retrieval and decoding system. And on Earth, all of life — from pond scum to peregrine falcons — evolved to use a single system. Every organism decodes DNA using the same 64 codons (three-letter combinations of the DNA bases known as A’s, T’s, C’s, and G’s)  to specify which of the 20 amino acids are going into the proteins it makes. Which means there are redundancies.  So, TCA, for example, tells the cell to grab an amino acid called serine and stick it next in the chain of whatever protein it’s building. But so does TCT. And AGT. In fact, there are six codons that all specify serine.  For years, Jason Chin, a molecular biologist at the MRC lab who led the new study, worked to whittle down some of those redundant codons and assign them new functions. Previously he and his team had systematically eliminated three codons across their E. coli’s genome, creating a bacteria, dubbed Syn61, that lived and squirmed and formed colonies despite using 61 codons rather than nature’s 64. But Syn61 still possessed the genetic program for creating all the molecules that actually read the codons and shuttle the correct amino acid to the site of protein production. These critical decoding molecules are called transfer ribonucleic acids, or tRNAs. In their latest work, Chin and his colleagues went through and deleted the tRNAs that recognize the codons they had already removed. The exercise wasn’t just about further streamlining their synthetic genome. Viruses don’t have any of their own decoding or protein production machinery. They rely on a host cell to do that. And in theory, if a virus invaded a bacteria that didn’t have the ability to read all of the codons in the viral genome, it would stymie the would-be hijacker’s plans for self-replication.  “The hypothesis was that the cells should be completely resistant to viruses,” said Chin. And indeed, that’s exactly what his team found. When mixed together with a cocktail of five different bacteriophages — viruses that prey on bacteria — their genetically reformulated E. coli rebuffed the viral onslaught. Eliminating the tRNAs was crucial. Colonies of their original synthetic strain, Syn61, were blasted apart by the phage invaders.

In what outside experts called the most rigorous and comprehensive survey of bacteria in human tumor samples, scientists have discovered distinct populations of microbes living inside different types of tumors: In other words, breast and brain and pancreatic tumors have their own characteristic microbiomes.

Recent research has revealed an intriguing relationship between microbes and cancer, including how bacteria in the gut can affect the way immunotherapies like checkpoint inhibitors or even standard chemotherapy work to shrink tumors. Now the new paper suggests the bacterial communities within tumors could be exploited to devise a new form of targeted therapies, in the same way we now develop drugs based on the molecular features of a tumor...

Original Research Published in Science ( May 29, 2020):

https://doi.org/10.1126/science.aay9189