Trillions of microbes live in the digestive tract alone, a menagerie estimated to contain more than 1,000 species that are mostly benign, or even beneficial, to us humans. — TNS
Inside every human is a thriving zoo of bacteria, fungi, viruses and other microscopic organisms collectively known as the microbiome.
Trillions of microbes live in the digestive tract alone – a menagerie estimated to contain more than 1,000 species.
This ecosystem of tiny stuff affects our health in ways science is only beginning to understand, including facilitating digestion, metabolism, the immune response and more.
But when serious infection sets in, the most powerful antibiotics take a merciless approach, wiping out not only the offensive microorganisms, but also colonies of beneficial bacteria in the digestive tract, often prompting secondary health problems.
“Increasingly, researchers are recognising the benefits of protecting the human gut microbiome, particularly because its integrity and diversity is linked to metabolic influences on mental health and physical health conditions,” says University of California Irvine population health and disease prevention professor Dr Oladele A. Ogunseitan.
Drug-resistant bugs are evolving faster than new medicines are being developed, rendering the current arsenal of medicines increasingly ineffective.
But the more we understand about the microbiome, the clearer it is that we need antibiotics that are discerning in their targets.
With that goal in mind, a chemistry team at the University of Illinois Urbana-Champaign (Urbana-Champaign) in the United States is experimenting with a compound that attempts to address both problems.
The antibiotic, lolamicin, both successfully vanquished several drug-resistant pathogens in mice while sparing the animals’ microbiome.
The results were published in the journal Nature.
“Only recently has it been recognised that killing these [beneficial] bacteria is having many deleterious effects on patients,” says study co-lead investigator and chemistry professor Dr Paul J. Hergenrother.
“We have been interested for some time in finding antibiotics that would be effective without killing the good bacteria.”
The team set out to create an antibiotic that would both preserve the gut microbiome while targeting gram-negative bacteria – a particularly hardy category of superbugs.
Encased in both an inner and outer membrane that antibiotics struggle to cross, gram-negative bacteria are resistant to most currently-available therapies.
Targeting Lol
Worldwide, antimicrobial resistance kills an estimated 1.27 million people directly every year and contributes to the deaths of millions more.
Not all gram-negative bugs make us sick.
Bacteria populations in the average human gut are roughly split between gram-negative and gram-positive types, says study co-lead investigator Dr Kristen Munoz, who completed her PhD at Urbana-Champaign last year (2023).
Broad spectrum antibiotics can’t tell which bugs to spare, she says.
As a result, anything strong enough to treat a bad infection “is going to wipe out a good amount of your gut microbiome”, even though they “aren’t doing anything 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 in gram-negative bacteria.
The Lol system’s genetic code looks different in harmful bacteria than it does in beneficial ones, which suggested to researchers that medicines that targeted the Lol system would be able to distinguish good bugs from bad ones.
The team designed multiple versions of these Lol-inhibiting compounds.
When tested against 130 drug-resistant strains of Escherichia coli, Klebsiella pneumoniae and Enterobacter cloacae, one in particular proved especially potent.
They tested this antibiotic, which they named lolamicin, on mice that had been infected with drug-resistant bacterial strains that cause septicaemia or pneumonia.
All of the mice with septicaemia 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 of two common antibiotics, i.e. amoxicillin and clindamycin.
After collecting baseline stool samples, they sampled the animals’ poop seven, 10 and 31 days after treatment.
Mice treated with amoxicillin or clindamycin had lower beneficial bacteria counts and less diversity of gut bacteria.
In contrast, the guts of lolamicin-treated mice appeared largely the same.
“It was exciting to see that lolamicin did not really cause any changes in the microbiome, whereas the other clinically-used antibiotics did,” Dr Munoz says.
More work to be done
A disrupted microbiome can have immediate consequences for people battling infection.
When beneficial microbes are decimated, dangerous bugs have fewer competitors and secondary infections can take hold.
Clostridium difficile is a notoriously opportunistic pathogen, so the researchers did an experiment where they exposed mice treated with lolamicin, amoxicillin or clindamycin to the bacterium.
The mice who took standard antibiotics were soon crawling with C. difficile.
The lolamicin mice showed little to no infection.
The lab hopes to one day take lolamicin or a version of it to clinical trials, Prof Hergenrother said.
Yet, these are still early days for the drug.
While the concept of a discerning antibiotic is a welcome development, it must clear significant barriers before it could make a difference for patients.
“Distinguishing a ‘bad bug’ from a ‘good bug’ is not always as straightforward as it may seem,” says Stanford University gastroenterologist and physician scientist Dr Sean Spencer, who was not involved with the research.
Some beneficial bugs in the gut bear a striking genetic resemblance to harmful pathogens, he says.
Others are benign in some contexts and dangerous in others: “In a critically-ill individual, a good bug can do bad things.”
Years can pass between a new antibiotic’s proof of concept and its entry 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 is perhaps the most formidable obstacle that lolamicin or any new antibiotic faces.
“One of the biggest problems is that bacteria are so smart.
“You can tackle one particular protein system or protein target in bacteria, but they will quickly find a resistance mechanism,” says Dr Munoz, who now works as a scientific analyst in Los Angeles.
“They just have so many inherent mechanisms to overcome antibiotics.” – By Corinne Purtill/Los Angeles Times/Tribune News Service
