A new effective antibiotic that cares for intestinal health

Spain’s National Plan to Combat Antibiotic Resistance (PRAN) indicates that multidrug-resistant bacteria cause 33,000 deaths per year in Europe and generate additional health care costs of €1.5 billion annually. Although this is a natural occurrence, abuse of these drugs in humans and animals accelerates this process. This week’s magazine Nature publishes investigator-led research Paul Hergenrother from the University of Illinois (USA), which showed a new antibiotic capable of reducing or eliminating drug-resistant bacterial infections in mouse models of acute pneumonia and sepsis, while maintaining healthy microbes in their gut.

The drug, called lolamycinand also prevents secondary infections due to Clostridioides difficilea common and dangerous nosocomial bacterial infection, and has been effective against more than 130 strains of multidrug-resistant bacteria in cell cultures..

Antibiotics are used to prevent and treat bacterial infections. Over time, these microorganisms mutate in response to drugs and become resistant to them, causing diseases that are more difficult to treat.

“There is an urgent need to change the way antibiotics are prescribed and used. Even if new drugs are developed, unless current behavior is changed, resistance will continue to pose a serious threat,” says WHO. On May 17, the institution updated the list of the most dangerous drug-resistant bacteria to human health, which included 15 families of these pathogens.

Antibiotics of last resort

To date, numerous studies have shown that gut microbiome changes Antibiotic-associated infections increase vulnerability to new infections and are associated with gastrointestinal, kidney, liver and other problems.

“The antibiotics we take, which fight infections and in some cases save our lives, also have harmful effects on us,” says Hergenrother, who co-led the study with Kristen Munozformer doctoral student.

“Unfortunately, these medications also kill the good bacteria in our gut, which causes various problems. Our new compound fights pathogens in rodents, but does not kill others,” says the lead author.

For his part, Muñoz points out that most antibiotics approved in clinical practice “kill only gram-positive bacteria or kill both gram-negative bacteria and gram-positive bacteria.”

The researcher points out how different they are in the composition of their cell walls: “Gram-negative bacteria have a double layer of defense, which makes them difficult to kill.” Actually, there are few drugs to combat these infections They also kill other potentially beneficial bacteria.

For example, colistin, one of the few exclusively gram-negative antibiotics approved for clinical use, can cause diarrhea associated with C. difficult and pseudomembranous colitis, a life-threatening complication. The drug also has toxic effects on the liver and kidneys, so “it is often used as an antibiotic of last resort,” the researchers wrote.

Effects of lolamycin

To address many of the problems associated with indiscriminately targeting gram-negative bacteria, the team focused on a combination of drugs developed by the pharmaceutical company AstraZeneca.

These drugs suppress lol system, responsible for the transport of lipoproteins that are exclusive to gram-negative bacteria and genetically different in pathogenic and beneficial microbes. These drugs were not effective against Gram-negative infections unless the researchers first subverted key bacterial defense mechanisms in the laboratory.

“However, since these antibiotics were found to be able to distinguish between beneficial and pathogenic Gram-negative bacteria in cell culture experiments, they became promising candidates for further research,” emphasizes Hergenrother.

In a series of experiments, Muñoz developed structural variants of Lol inhibitors and assessed their potential against Gram-negative and Gram-positive bacteria in cell cultures. As the authors note, lolamycin selectively targeted against certain “laboratory strains of Gram-negative pathogens, such as coli, Klebsiella pneumonia And Enterobacter cloaca“

Lolamycin had no significant effect on gram-positive bacteria in cell culture, but at high doses it killed up to 90% of clinical strains of these three species.Escherichia coli, K. pneumoniae And E. cloaca) multidrug resistance.

When administered orally to mice with drug-resistant sepsis or pneumonia lolamycin saved 100% of mice with the first and 70% of mice with the second.

Increasing antibiotic resistance

The team found that treatment with standard antibiotics amoxicillin and clindamycin caused radical changes in the overall structure of bacterial populations in the intestines of mice, reducing the abundance of several beneficial groups of microbes.

“On the contrary, lolamycin did not cause dramatic changes in taxonomic composition neither during three days of treatment, nor in the subsequent 28 days of recovery,” the scientists say.

“This antibiotic hits a different target than all the approved compounds, and in our experiments even kills multi-resistant bacteria,” Hergenrother insists in an interview with SINC. Of course, ‘this connection and this approach They have yet to be evaluated in human clinical trials.“

Lolamycin or other similar compounds should be tested with more bacterial strains and conduct detailed toxicological studies. “Any new antibiotic also needs to be evaluated to determine how quickly it induces drug resistance, a problem that sooner or later arises in bacteria treated with antibiotics,” he concludes.

Link:

Kristen A. Muñoz et al. “Gram-negative selective antibiotic spares the gut microbiome.” Nature 2024