Researchers have created a new antibiotic, lolamicin, that successfully treated drug-resistant bacterial infections in mouse models of acute pneumonia and sepsis. It also spared healthy microbes in the mouse gut and prevented secondary infections with Clostridioides difficile, a common and hazardous hospital-associated bacterial infection. In addition, lolamicin was effective against over 130 multidrug-resistant bacterial strains in cell culture.The drug, lolamicin, was found to protect healthy microbes in the mouse gut and prevent secondary infections with Clostridioides difficile, a common and dangerous hospital-associated bacterial infection. It was also effective against over 130 multidrug-resistant bacterial strains in cell culture. These findings are detailed in the journal Nature. According to the University of Illinois Urbana-Champaign, people are starting to realize that while antibiotics are essential in fighting infections and saving lives, they also have negative effects on our bodies.Chemistry professor Paul Hergenrother, along with former doctoral student Kristen Muñoz, conducted a study on the effects of antibiotics on the body’s good bacteria. According to Hergenrother, “They’re killing our good bacteria as they treat the infection. We wanted to start thinking about the next generation of antibiotics that could be developed to kill the pathogenic bacteria and not the beneficial ones.” Various research studies have shown that disruptions to the gut microbiome caused by antibiotics can lead to an increased susceptibility to infections and are linked to gastrointestinal, kidney, liver, and other health issues. Hergenrother also noted that most clinically approved antibiotics only target gram-positive bacteria or both gram-positive and gram-negative bacteria.
“Gram-negative bacteria are a type of bacteria that are more difficult to kill due to their double layer of protection,” explained Muñoz. “This makes them a challenging target for drug treatments.” On the other hand, gram-positive bacteria have a different cell wall composition.
Unfortunately, the limited drugs available to combat gram-negative infections also have negative effects on potentially beneficial bacteria. For instance, colistin, which is one of the few antibiotics approved for clinical use against gram-negative bacteria, can lead to complications such as C. difficile-associated diarrhea and pseudomembranous colitis, both of which can be life-threatening. In addition, the drug can be toxic to the liver and kidneys,” clarified Muñoz.Colistin is usually reserved as a last resort antibiotic, according to the researchers. In order to address the issues related to indiscriminate targeting of gram-negative bacteria, the team concentrated on a group of drugs created by AstraZeneca. These drugs target the Lol system, a specific lipoprotein-transport system found only in gram-negative bacteria and genetically distinct from pathogenic and beneficial microbes. The drugs proved to be ineffective against gram-negative infections unless the researchers first weakened important bacterial defenses in the lab.According to Hergenrother, these antibiotics seemed to be able to distinguish between helpful and harmful gram-negative bacteria in lab tests, making them good candidates for further research.
Muñoz conducted a series of experiments where he created different versions of the Lol inhibitors and tested their ability to combat both gram-negative and gram-positive bacteria in cell cultures. One of the new compounds, lolamicin, specifically targeted certain strains of gram-negative pathogens such as Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae, the researchers discovered.
Lolamicin had no discernible impact on gram-positive bacteria in cell culture. However, at higher concentrations, it was able to eliminate up to 90% of multidrug-resistant strains of E. coli, K. pneumoniae, and E. cloacae that were isolated from clinical sources.
In experiments involving mice with drug-resistant septicemia or pneumonia, oral administration of lolamicin resulted in the rescue of all mice with septicemia and 70% of those with pneumonia, according to the research team.
The researchers conducted extensive investigations to evaluate the effects of lolamicin on the gut microbiome.
According to Muñoz, “The mouse microbiome serves as an effective model for studying human infections due to the remarkable similarity between the gut microbiomes of humans and mice. Studies have shown that lolamicin had no detectable effect on gram-positive bacteria in cell culture. At higher doses, lolamicin killed up to 90% of multidrug-resistant E. coli, K. pneumoniae and E. cloacae clinical isolates.
When given orally to mice with drug-resistant septicemia or pneumonia, lolamicin rescued 100% of the mice with septicemia and 70% of the mice with pneumonia, the team reported.
Extensive work was done to determine the effect of lolamicin on the gut microbiome.
“The mouse microbiome is a good tool for modeling human infections because human and mouse gut microbiomes are very similar,” Muñoz said. “Studies ha ve demonstrated that the microbiome of mice is an effective tool for modeling human infections due to the high degree of similarity between the two.Researchers have demonstrated that antibiotics that disrupt gut bacteria in mice have a comparable impact on humans. The usage of standard antibiotics like amoxicillin and clindamycin led to significant changes in the overall structure of bacterial populations in the mouse gut, reducing the abundance of several beneficial microbial groups. However, lolamicin did not cause major changes in the composition of bacteria during the treatment or the subsequent recovery period. According to the researchers, additional years of research are required to expand on these findings. This could involve exploring lolamicin or similar compounds further.The effectiveness of new antibiotics needs to be tested against a wider range of bacterial strains and thorough toxicology studies are necessary. It is also important to assess how quickly the antibiotics lead to drug resistance in bacteria. This study shows that there is potential to develop antibiotics that can selectively kill harmful microbes while leaving beneficial gut bacteria unharmed, particularly for challenging gram-negative infections. Hergenrother, the author, emphasized the significance of this proof-of-concept.
