Inside every human lives a thriving zoo of bacteria, fungi, viruses, and other microscopic organisms, collectively referred to as the microbiome. The digestive tract alone is home to trillions of microbes, a menagerie estimated to incorporate greater than 1,000 species.
This ecosystem of tiny things affects our health in ways in which science is just starting to know. It facilitates digestion, metabolism, immune response, and far more. But when a serious infection occurs, probably the most powerful antibiotics are merciless: They destroy colonies of useful bacteria within the digestive tract and infrequently result in secondary health problems.
“Researchers are increasingly recognizing the benefits of protecting the human gut microbiome, particularly because its integrity and diversity is linked to metabolic influences on mental and physical health,” said Oladele A. Ogunseitan, Ph.D., professor of population health and disease prevention at UC Irvine.
Drug-resistant germs are develop faster as latest drugs are developed, rendering the present arsenal of medication increasingly ineffective. But the more we understand in regards to the microbiome, the clearer it becomes that we want antibiotics that specifically goal the disease.
With this goal in mind, a chemistry team on the University of Illinois Urbana-Champaign is experimenting with a compound that goals to deal with each problems. The antibiotic lolamicin successfully defeated several drug-resistant pathogens in mice while sparing the animals' microbiome. The results were published within the journal Nature.
“It was only recently that it was recognized that killing these [beneficial] “Bacteria have many harmful effects on patients,” said Paul J. Hergenrother, a chemistry professor on the University of Illinois Urbana-Champaign who co-led the study. “We have been interested for some time in finding antibiotics that are effective without killing the good bacteria.”
Worldwide, Antimicrobial resistance kills an estimated 1.27 million people directly annually and contributes to the deaths of thousands and thousands more.
Not all gram-negative bacteria make us sick. The bacterial populations in the common human gut could be roughly divided into gram-negative and gram-positive types, says Kristen Munoz, a former doctoral student on the University of Illinois who co-led the study.
Broad-spectrum antibiotics can't tell which bacteria to spare, she said, so any agent strong enough to treat a serious infection will “wipe out a lot of your gut microbiome,” she said, despite the fact that it's “not doing anything bad.”
The team focused its seek for a brand new drug on compounds that suppress the Lol system, which transports lipoproteins between the inner and outer membranes of Gram-negative bacteria.
The genetic code of the Lol system looks different in harmful bacteria than in useful ones. This suggested to the researchers that drugs targeting the Lol system would have the option to differentiate good bacteria from bad ones.
The team developed several versions of those Lol-inhibiting compounds, and one in every of them proved particularly effective when tested against 130 drug-resistant strains of Escherichia coli, Klebsiella pneumoniae and Enterobacter cloacae.
They tested this antibiotic, which they called lolamicin, on mice infected with drug-resistant strains of sepsis or pneumonia. All of the mice with sepsis survived after receiving lolamicin, as did 70% of the mice with pneumonia.
To measure the effect on gut bacteria, the researchers gave healthy mice either lolamicin, a placebo, or one in every of two common antibiotics, amoxicillin and clindamycin. After collecting stool samples, they examined the animals' feces seven, ten, and 31 days after treatment.
In mice treated with amoxicillin or clindamycin, the variety of useful bacteria was lower and the gut bacteria were less diverse. In contrast, the center of mice treated with lolamycin gave the impression to be largely the identical.
“It was exciting to see that lolamicin did not cause any real changes in the microbiome, whereas the other antibiotics used clinically did,” Munoz said.
A disrupted microbiome can have immediate consequences for people battling an infection. When useful microbes are decimated, dangerous bacteria have less competition and secondary infections can spread.
Clostridium difficile is a notorious opportunistic pathogen, so the researchers conducted an experiment wherein they exposed mice treated with lolamicin, amoxicillin, or clindamycin to C. difficile. The mice that received standard antibiotics soon became infected with C. difficile. The lolamicin mice showed little to no infection.
The lab hopes to in the future test lolamicin or a version of it in clinical trials, Hergenrother said. (Munoz earned her PhD last yr and now works as a research analyst in Los Angeles.) But the drug remains to be in its infancy. While the concept of a targeted antibiotic is a welcome development, significant hurdles still must be overcome before it will possibly make a difference for patients.
“Distinguishing a so-called 'bad virus' from a so-called 'good virus' is not always as easy as it seems,” said Dr. Sean Spencer, a gastroenterologist and physician at Stanford University who was not involved within the research.
Some useful bacteria within the gut show a striking genetic similarity to harmful pathogens, he said. Others are harmless in some contexts and dangerous in others: “In a seriously ill person, a good germ can do bad things.”
Years can pass between a brand new antibiotic's proof of concept and its launch available on the market, and the overwhelming majority never make it to the top of that pipeline. It's also not clear how easily or how quickly bacteria develop resistance, which is maybe the most important obstacle facing lolamicin or any latest antibiotic.
“One of the biggest problems is that bacteria are so smart. You can attack a specific protein system or protein target in bacteria, but they will quickly find a resistance mechanism,” Munoz said. “They just have so many inherent mechanisms to overcome antibiotics.”
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