Science Paper Interpretation! Changes in metabolic state make bacteria resistant to antibiotics...

Bacteria have many ways to escape the antibiotics we use to deal with them.
at least 2.8 million people in the U.S. develop antibiotic-resistant infections each year, and more than 35,000 die from them, according to the Centers for Disease Control (CDC).
most known drug-resistant mutations occur in genes targeted by specific antibiotics.
other drug-resistant mutations allow bacteria to break down antibiotics or pump them out through their cell membranes.
a new study, researchers at the Massachusetts Institute of Technology in the United States have now identified another type of mutation that helps bacteria develop resistance.
study of E. coli, they found that genetic mutations involved in metabolism can also help bacteria escape the toxic effects of several different antibiotics.
say the findings shed light on a fundamental aspect of how antibiotics work and suggest potential new ways to develop drugs that could enhance the effectiveness of existing antibiotics.
study was published in the February 19, 2021 issue of the Journal of Science under the title "Clinically relevant mutations in core metabolic genes confer antibiotic resistance".
metabolic state leads to antibiotic resistance, pictured is Science, 2021, doi:10.1126/science.aba0862.
This study provides us with new insights into how to improve the effectiveness of existing antibiotics because it emphasizes the important role of downstream metabolism," said Professor James Collins of the Massachusetts Institute of Medical Engineering and Science, co-author of the paper.
specifically, our research shows that if the metabolic response of the treated pathogen can be improved, the effectiveness of antibiotics can be enhanced.
" Metabolic Control, based on previous research in Collins' lab, shows that when treated with antibiotics, many bacteria are forced to speed up metabolism, leading to the accumulation of toxic by-products.
these by-products can damage bacterial cells and cause them to die.
, however, that although overactive metabolism plays a role in bacterial cell death, scientists have found no evidence that this metabolic stress causes mutations that help bacteria produce antibiotic-escaping drugs.
Collins and the paper's lead author, Allison Lopatkin, a former postdoctoral researcher at the Massachusetts Institute of Technology, began studying whether such mutations could be found.
, they conducted a study similar to the one commonly used to find mutations in antibiotic resistance.
in this type of screening, called adaptive evolution, the researchers began studying the E. coli strain in the lab and then treated bacterial cells with specific antibiotics that gradually increased in dose.
, they sequenced the genomes of bacterial cells to see what mutations had developed during treatment.
the number of genes that can be sequenced is limited, this method has not previously found mutations in genes involved in metabolism.
Lopatkin said, "Many previous studies have looked at evolutionary cloning, or sequencing some of the genes we expect to mutate, because they are related to the way antibiotic drugs work.
allows us to understand these drug-resistant genes accurately, but this limits our perception of anything else.
, for example, the antibiotic ciprofloxacin targets DNA cyclase--- an enzyme involved in DNA replication that forces the enzyme to destroy the DNA of cells.
when treated with cyclopropylsacin, bacterial cells often produce mutations in genes that encode DNA cyclotrase, allowing them to evade the drug's mechanisms of effect.
their first adaptive evolutionary screening, the researchers analyzed more E. coli cells and more genes than previously studied.
allowed them to identify mutations in 24 metabolic genes, including those associated with amino acid metabolism and carbon cycling.
in the carbon cycle, a series of chemical reactions allow cells to extract energy from sugar and release carbon dioxide as a by-product.
to screen for more metabolic-related mutations, the researchers conducted a second screening in which they forced bacterial cells into a highly metabolic state.
these experiments, E. coli was treated with a high concentration of antibiotics every day, and the temperature gradually increased.
temperature gradually pushed these bacterial cells into a very active metabolic state, and at the same time, they gradually developed resistance to cyclopropylsacin.
the researchers then sequenced the genomes of the bacteria and found some metabolic-related mutations they saw in the first screening, as well as other mutations in metabolic genes.
these genes, in addition to those involved in the carbon cycle, include genes involved in amino acid synthesis, especially glutamate.
, they compared the results with a genome bank of drug-resistant bacteria isolated from patients and found many of the same mutations.
the new targets, the researchers genetically modified the typical E. coli strain to carry some of these mutations, only to find that their cells breathing rate decreased significantly.
when they treat these bacterial cells with antibiotics, they need a larger dose to kill them.
suggests that by reducing their metabolism after drug treatment, these bacteria can prevent the accumulation of harmful by-products.
the findings raise the possibility that forcing bacteria into a highly metabolic state could improve the effectiveness of existing antibiotics, the researchers said.
now plan to further study how these metabolic mutations help bacteria evade antibiotics and hope to provide more specific targets for the development of new complementary drugs.
These results are really exciting because they reveal genetic targets that may improve the efficacy of antibiotics that have not yet been studied," Lopatkin said.
new drug resistance mechanisms are really exciting because they provide many new avenues for follow-up studies and see to what extent this can improve the efficacy of targeted clinical strains.
" (Biogu Bioon.com) Reference: 1. Allison J. Lopatkin et al. Clinically relevant mutations in core metabolic genes confer antibiotic resistance. Science, 2021, doi:10.1126/science.aba0862.2.Mattia Zampieri. The genetic underground of antibiotic resistance. Science, 2021, doi:10.1126/science.abf7922.metabolic mutations help bacteria resist drug treatment This article is sourced from Bio Valley, for more information please download Bio Valley APP (