Inside every person is a thriving zoo of bacteria, fungi, viruses and other microscopic organisms, collectively known as the microbiome. The digestive tract alone is home to trillions of microbes, a menagerie estimated to contain more than 1,000 species.
This ecosystem of little things influences our health in ways that science is only beginning to understand, facilitating digestion, metabolism, immune response and more. But when a serious infection occurs, the most powerful antibiotics take a brutal approach, wiping out colonies of beneficial bacteria in the digestive tract and often prompting secondary health problems.
“Researchers are increasingly recognizing the benefits of protecting the human gut microbiome, especially as its integrity and diversity are linked to metabolic influences on mental and physical health,” said Dr. Oladele A. Ogunseitan, professor of public health and disease. prevention at UC Irvine.
Drug-resistant insects are evolve faster than new medications are developed, making the current arsenal of medications increasingly ineffective. But the more we understand about the microbiome, the clearer it is that we need antibiotics that are distinctive in their targets.
To that end, a chemistry team from the University of Illinois Urbana-Champaign is experimenting with a compound that attempts to address both problems. The antibiotic, lolamicin, both successfully overcame several drug-resistant pathogens in mice, while sparing the animals' microbiome. The results were published in the journal Nature.
“It is only recently that the killing of these people has been recognized [beneficial] bacteria have many harmful effects on patients,” said Paul J. Hergenrother, professor of chemistry at the University of Illinois Urbana-Champaign, who co-led the study. “We have been interested for some time in finding antibiotics that would be effective without killing the good bacteria.”
The team wanted to create an antibiotic that would both preserve the gut microbiome and target gram-negative bacteria, a particularly potent category of superbugs. Gram-negative bacteria are encapsulated in both an inner and outer membrane that is difficult for antibiotics to penetrate and are resistant to most currently available therapies. They are responsible for the majority of the estimated 35,000 deaths in the US each year from drug-resistant infections. according to to the US Centers for Disease Control and Prevention.
Globally, antimicrobial resistance kills an estimated 1.27 million people directly each year and contributes to the deaths of millions more.
Not all gram-negative bugs make us sick. Bacteria populations in the average human intestine are roughly divided between gram-negative and gram-positive types, said Kristen Munoz, a former doctoral student at the University of Illinois who co-led the study.
Broad-spectrum antibiotics can't determine which insects to spare, she said. As a result, anything strong enough to treat a serious infection will “wipe out a big chunk of your gut microbiome,” she said, even though they're doing “nothing wrong.”
The team focused its search for a new drug on compounds that suppress the Lol system, which shuttles 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 beneficial bacteria, suggesting to researchers that drugs targeting the Lol system could distinguish good from bad bacteria.
The team designed multiple versions of these Lol-inhibiting compounds. When tested against 130 resistant strains of Escherichia coli, Klebsiella pneumoniae And Enterobacter cloacaeone of them turned out to be particularly powerful.
They tested this antibiotic, which they called lolamicin, on mice infected with resistant strains of blood poisoning or pneumonia. All mice with sepsis survived after administration of lolamicin, as did 70% of the mice with pneumonia.
To measure the effect on intestinal bacteria, the researchers gave healthy mice lolamicin, a placebo or one of two common antibiotics, amoxicillin and clindamycin. After collecting baseline fecal samples, they sampled the animals' poop seven, 10 and 31 days after treatment.
Mice treated with amoxicillin or clindamycin had lower numbers of beneficial bacteria and a lower diversity of intestinal bacteria. In contrast, the intestines of lolamicin-treated mice looked largely the same.
“It was exciting to see that lolamicin didn't actually cause changes in the microbiome, while the other clinically used antibiotics did,” Munoz said.
A disrupted microbiome can have immediate consequences for people struggling with infections. When beneficial microbes are decimated, dangerous insects have fewer competitors and secondary infections can take hold.
Clostridium difficile is a notorious opportunistic pathogen, so the researchers did an experiment in which they exposed mice treated with lolamicin, amoxicillin or clindamycin to C. difficult. The mice that took standard antibiotics soon became swarming with them C. difficult. The lolamicin mice showed little to no infection.
The lab hopes to one day take lolamicin or a version of it into clinical trials, Hergenrother said. (Munoz received his PhD last year and now works as a scientific analyst in Los Angeles.) Still, these are still early years for the drug. While the concept of a distinctive antibiotic is a welcome development, it must remove significant barriers before it can make a difference for patients.
“Distinguishing between a 'bad bug' without quotes and a 'good bug' without quotes is not always as easy as it seems,” says Dr. Sean Spencer, a gastroenterologist and physician-scientist at Stanford University who was not involved in the study. .
Some beneficial insects in the gut bear a striking genetic similarity to harmful pathogens, he said. Others are benign in some contexts and dangerous in others: “In a seriously ill individual, a good bug can do bad things.”
Years can pass between a new antibiotic's proof of concept and its introduction to the market, and the vast majority never make it to the end of that pipeline. It's also not clear how easily or how quickly bacteria will develop resistance, which may be the biggest obstacle facing lolamicin or any new antibiotic.
“One of the biggest problems is that bacteria are so smart. You can target one particular protein system or protein target in bacteria, but they will quickly find a resistance mechanism,” says Munoz. “They just have so many inherent mechanisms to overcome antibiotics.”
