A new antibiotic uses a never-before-seen mechanism to deliver a direct hit on tough-to-treat infections while leaving beneficial microbes alone. The strategy could lead to a new class of antibiotics that attack dangerous bacteria in a powerful new way, overcoming current drug resistance while sparing the gut microbiome.
"The biggest takeaway is the double-selective component," said co-lead author Kristen A. Muñoz, PhD, who performed the research as a doctoral student at University of Illinois at Urbana-Champaign (UIUC). "We were able to develop a drug that not only targets problematic pathogens, but because it is selective for these pathogens only, we can spare the good bacteria and preserve the integrity of the microbiome."
The drug goes after Gram-negative bacteria — pathogens responsible for debilitating and even fatal infections like gastroenteritis, urinary tract infections, pneumonia, sepsis, and cholera. The arsenal of antibiotics against them is old, with no new classes specifically targeting these bacteria coming on the market since 1968.
Many of these bugs have become resistant to one or more antibiotics, with deadly consequences. And antibiotics against them can also wipe out beneficial gut bacteria, allowing serious secondary infections to flare up.
In a study published on May 29 in Nature, the drug lolamicin knocked out or reduced 130 strains of antibiotic-resistant Gram-negative bacteria in cell cultures. It also successfully treated drug-resistant bloodstream infections and pneumonia in mice while sparing their gut microbiome.
With their microbiomes intact, the mice then fought off secondary infection with Clostridioides difficile (a leading cause of opportunistic and sometimes fatal infections in US healthcare facilities), while mice treated with other compounds that damaged their microbiome succumbed.
How It Works
Like a well-built medieval castle, Gram-negative bacteria are encased in two protective walls, or membranes. Muñoz and her team at UIUC set out to breach this defense by finding compounds that hinder the "Lol system," which ferries lipoproteins between them.
From one compound they constructed lolamicin, which can stop Gram-negative pathogens — with little effect on Gram-negative beneficial bacteria and no effect on Gram-positive bacteria.
"Gram-positive bacteria do not have an outer membrane, so they do not possess the Lol system," Muñoz said. "When we compared the sequences of the Lol system in certain Gram-negative pathogens to Gram-negative commensal [beneficial] gut bacteria, we saw that the Lol systems were pretty different."
Tossing a monkey wrench into the Lol system may be the study's biggest contribution to future antibiotic development, said Kim Lewis, PhD, Professor of Biology and director of Antimicrobial Discovery Center at Northeastern University, Boston, who has discovered several antibiotics now in preclinical research. One, darobactin, targets Gram-negative bugs without affecting the gut microbiome. Another, teixobactin, takes down Gram-positive bacteria without causing drug resistance.
"Lolamicin hits a novel target. I would say that's the most significant study finding," said Lewis, who was not involved in the study. "That is rare. If you look at antibiotics introduced since 1968, they have been modifications of existing antibiotics or, rarely, new chemically but hitting the same proven targets. This one hits something properly new, and [that's] what I found perhaps the most original and interesting."
Kirk E. Hevener, PharmD, PhD, Associate Professor of Pharmaceutical Sciences at the University of Tennessee Health Science Center, Memphis, Tennessee, agreed. (Hevener also was not involved in the study.) "Lolamicin works by targeting a unique Gram-negative transport system. No currently approved antibacterials work in this way, meaning it potentially represents the first of a new class of antibacterials with narrow-spectrum Gram-negative activity and low gastrointestinal disturbance," said Hevener, whose research looks at new antimicrobial drug targets.
The UIUC researchers noted that lolamicin has one drawback: Bacteria frequently developed resistance to it. But in future work, it could be tweaked, combined with other antibiotics, or used as a template for finding other Lol system attackers, they said.
"There is still a good amount of work cut out for us in terms of assessing the clinical translatability of lolamicin, but we are hopeful for the future of this drug," Muñoz said.
Addressing a Dire Need
Bringing such a drug to market — from discovery to Food and Drug Administration approval — could take more than a decade, said Hevener. And new agents, especially for Gram-negative bugs, are sorely needed.
Not only do these bacteria shield themselves with a double membrane but they also "have more complex resistance mechanisms including special pumps that can remove antibacterial drugs from the cell before they can be effective," Hevener said.
As a result, drug-resistant Gram-negative bacteria are making treatment of severe infections such as sepsis and pneumonia in healthcare settings difficult.
Bloodstream infections with drug-resistant Klebsiella pneumoniae have a 40% mortality rate, Lewis said. And microbiome damage caused by antibiotics is also widespread and deadly, wiping out communities of helpful, protective gut bacteria. That contributes to over half of the C difficile infections that affect 500,000 people and kill 30,000 a year in the United States.
"Our arsenal of antibacterials that can be used to treat Gram-negative infections is dangerously low," Hevener said. "Research will always be needed to develop new antibacterials with novel mechanisms of activity that can bypass bacterial resistance mechanisms."