Antibiotics are medications intended to combat infections caused by bacteria and act by killing these pathogens, or inhibiting their growth and reproduction. They are also used as a way to prevent the development of an infection before certain medical procedures, such as surgery. But it is important to note that antibiotics are not effective against viral infections, such as a cold, the flu, or COVID.
Currently we have a public health problem worldwide due to their inappropriate or excessive use that has contributed to an increase in bacterial resistance, that is, bacteria develop mechanisms that counteract the effect of antibiotics, which has making many infections very difficult to treat.
Now, researchers at the University of Illinois at Urbana-Champaign have developed a new antibiotic that has reduced or eliminated drug-resistant bacterial infections in mouse models of acute pneumonia and sepsis while sparing healthy microbes in the intestine of these animals. The drug is called lolamycin and also prevented secondary infections from Clostridioides difficile – a serious common bacterial infection usually acquired in the hospital environment – and was effective against more than 130 multidrug-resistant bacterial strains in cell cultures.
Treatments that also eliminate beneficial bacteria
“People are starting to realize that the antibiotics we have been taking – which fight infections and, in some cases, save our lives – also have detrimental effects on us,” said Paul Hergenrother, a chemistry professor at the University. of Illinois in Urbana-Champaign, who led the study along with former doctoral student Kristen Muñoz.
“They are killing our good bacteria while treating the infection. “We wanted to start thinking about the next generation of antibiotics that could be developed to kill pathogenic bacteria and not beneficial bacteria,” he added. Numerous studies have found that alterations in the intestinal microbiome related to antibiotics increase vulnerability to new infections and are associated with gastrointestinal, kidney and liver problems, among others.
“Most clinically approved antibiotics only kill gram-positive bacteria, or they kill both gram-positive and gram-negative bacteria,” Muñoz said. Gram-positive and gram-negative bacteria differ in the composition of their cell walls. Gram-negative bacteria have a double layer of protection, and this makes them more difficult to eliminate, Muñoz explained.
Treatment with oral lolamycin allowed 100% of the mice with sepsis and 70% of the mice with pneumonia to recover.
The few drugs capable of fighting gram-negative infections also kill other potentially beneficial gram-negative bacteria. For example, colistin, one of the few antibiotics approved for clinical use only against gram-negatives, can cause C. difficile-associated diarrhea and pseudomembranous colitis, a life-threatening complication. The drug also has toxic effects on the liver and kidneys, and “therefore, colistin is typically used only as an antibiotic of last resort,” the researchers wrote.
A drug that kills pathogens without harming healthy microbes
To address the numerous problems associated with the indiscriminate elimination of gram-negative bacteria, the team focused on a series of drugs developed by the pharmaceutical company AstraZeneca. These drugs inhibit the Lol system, a lipoprotein transport system unique to gram-negative bacteria and genetically distinct in pathogenic and beneficial microbes.
These drugs were not effective against gram-negative infections unless researchers first undermined key bacterial defenses in the laboratory. But because these antibiotics appeared to distinguish between beneficial and pathogenic Gram-negative bacteria in cell culture experiments, they were promising candidates for further exploration, Hergenrother said.
Muñoz designed structural variations of Lol inhibitors and evaluated their potential to combat gram-negative and gram-positive bacteria in cell cultures through various experiments. The researchers found that one of the new compounds, lolamycin, selectively targeted some “laboratory strains of gram-negative pathogens, including Escherichia coli, Klebsiella pneumoniae and Enterobacter cloacae.”
Lolamycin had no detectable effect on gram-positive bacteria in cell cultures. At higher doses, lolamycin killed up to 90% of clinical isolates of multidrug-resistant E. coli, K. pneumoniae, and E. cloacae. When administered orally to mice with sepsis or drug-resistant pneumonia, lolamycin rescued 100% of the mice with sepsis and 70% of the mice with pneumonia, the team reported. Their findings are described in the journal Nature.
“The mouse microbiome is a good tool for modeling human infections because the human and mouse gut microbiomes are very similar,” Muñoz said. “Studies have shown that antibiotics that cause intestinal dysbiosis in mice have a similar effect in humans.”
Treatment with the standard antibiotics amoxicillin and clindamycin caused significant changes in the overall structure of bacterial populations in the intestine of mice and reduced the population of several beneficial microbial groups. “In contrast, lolamycin did not cause drastic changes in taxonomic composition during the three-day treatment course or during the subsequent 28 days of recovery,” the researchers wrote.
Many more years of research are needed to expand the findings, Hergenrother acknowledges, as lolamycin or other similar compounds must be tested against more bacterial strains and detailed toxicological studies must be performed. The study is proof of concept that antibiotics that kill a pathogenic microbe while preserving beneficial bacteria in the gut can be developed for gram-negative infections, which are some of the most difficult infections to treat, Hergenrother concludes.
