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A groundbreaking antibiotic, developed by researchers at the University of Illinois at Urbana-Champaign (UIUC), introduces a novel mechanism to combat stubborn infections without harming beneficial gut bacteria. This innovative approach could herald a new class of antibiotics capable of overcoming current drug resistance issues while preserving the gut microbiome’s integrity.
A Double-Selective Breakthrough
“The biggest takeaway is the double-selective component,” said Dr. Kristen A. Muñoz, co-lead author and former doctoral student at UIUC. “We developed a drug that not only targets problematic pathogens but also spares good bacteria, preserving the microbiome.”
The new antibiotic, lolamicin, specifically targets Gram-negative bacteria—pathogens responsible for severe infections such as gastroenteritis, urinary tract infections, pneumonia, sepsis, and cholera. Since 1968, no new antibiotic classes targeting these bacteria have reached the market, and existing drugs often cause collateral damage to beneficial bacteria, leading to dangerous secondary infections.
In a study published in Nature on May 29, lolamicin demonstrated its efficacy against 130 strains of antibiotic-resistant Gram-negative bacteria in cell cultures. It also successfully treated drug-resistant bloodstream infections and pneumonia in mice, without disrupting their gut microbiomes. This preservation allowed the mice to fend off secondary infections, such as Clostridioides difficile, a leading cause of opportunistic infections in healthcare facilities.
Unveiling a New Mechanism
Gram-negative bacteria are notoriously difficult to treat due to their double-membrane structure. The UIUC team discovered that lolamicin disrupts the “Lol system,” which transports lipoproteins between the bacteria’s membranes. This disruption proved lethal to Gram-negative pathogens while sparing beneficial Gram-negative bacteria and having no effect on Gram-positive bacteria.
“Gram-positive bacteria do not have an outer membrane, so they do not possess the Lol system,” Muñoz explained. “When we compared the sequences of the Lol system in certain Gram-negative pathogens to Gram-negative commensal gut bacteria, we saw significant differences.”
Dr. Kim Lewis, Professor of Biology and Director of the Antimicrobial Discovery Center at Northeastern University, praised the discovery. “Lolamicin hits a novel target. That is rare and significant,” said Lewis, who was not involved in the study. “Most antibiotics introduced since 1968 have been modifications of existing ones. This one hits something properly new, which is perhaps the most original and interesting aspect.”
Dr. Kirk E. Hevener, Associate Professor of Pharmaceutical Sciences at the University of Tennessee Health Science Center, concurred. “Lolamicin potentially represents the first of a new class of antibacterials with narrow-spectrum Gram-negative activity and low gastrointestinal disturbance,” said Hevener, who also was not involved in the study.
Challenges and Future Directions
Despite its promise, lolamicin has a notable drawback: bacteria frequently develop resistance to it. Future research will focus on tweaking the drug, combining it with other antibiotics, or using it as a template to discover other Lol system inhibitors.
“There is still much work to be done to assess the clinical translatability of lolamicin, but we are hopeful,” Muñoz said.
Addressing a Critical Need
Bringing a new antibiotic to market can take over a decade, but the need for new agents, especially for Gram-negative bacteria, is urgent. These bacteria’s double membrane and complex resistance mechanisms make treating severe infections like sepsis and pneumonia challenging.
Bloodstream infections with drug-resistant Klebsiella pneumoniae have a 40% mortality rate, according to Lewis. Additionally, damage to the microbiome caused by antibiotics contributes to over half of the Clostridioides difficile infections that affect 500,000 people and kill 30,000 annually in the United States.
“Our arsenal of antibacterials that can be used to treat Gram-negative infections is dangerously low,” Hevener warned. “Research will always be needed to develop new antibacterials with novel mechanisms that can bypass bacterial resistance.”
Lolamicin’s novel approach represents a significant step forward in the fight against antibiotic-resistant bacteria, offering hope for more effective and targeted treatments in the future.
