A new antibiotic based on drugs developed by AstraZeneca can kill off dangerous bacteria that cause sepsis and pneumonia without harming healthy gut microbes, research in mice shows. If further developed, drugs like it eventually could overcome a major downside to some antibiotics that is linked to serious complications.
In an article published May 29 in Nature, a team of scientists from the University of Illinois Urbana-Champaign presented data demonstrating that their antibiotic lolamicin could kill deadly bacterial strains in cells and mice without affecting beneficial gram-negative strains that colonize the gut.
“[Existing antibiotics are] killing our good bacteria as they treat the infection,” Paul Hergenrother, Ph.D., principal investigator on the study, said in a press release. “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.”
Lolamicin works by disrupting the activity of the Lol system, a transport system exclusive to gram-negative bacteria that moves lipoproteins from one part of the microbe to another. Its creation stemmed from a screening of compounds originally discovered by AstraZeneca, which was not involved in the research.
Although the researchers found that the drugs weren’t particularly good at inhibiting gram-negative bacteria unless the bugs’ defense systems were disarmed first, they were selective for “bad” strains over “good” ones found in the human gut. This made them a good starting place for creating antibiotics against tough-to-target gram-negative pathogens without hurting the helpful ones.
A few modifications and assays later, lolamicin was born. The researchers found that at high doses it could kill off as much as 90% of E. coli, K. pneumoniae and E. cloacae that had been taken from patient samples but had no effect against either gram-positive bacteria or the kinds of gram-negative bacteria that populate the human gut. It was also nontoxic to mammalian cell lines and red blood cells, their analysis showed.
Next, the researchers tested lolamicin in mouse models of sepsis and pneumonia caused by multidrug-resistant strains of E. coli., K. pneumoniae or E. cloacae. All of the mice with sepsis who were treated with the drug survived, along with 70% of those that had pneumonia. In contrast, most of the mice treated with a control solution or a comparison compound died within 48 hours.
The scientists then looked at whether the “good bacteria”-sparing qualities lolamicin exhibited in cell studies extended to animal models. They treated mice with lolamicin, amoxicillin or clindamycin at therapeutic doses for three days, then collected fecal samples at three different time points over the following month, which they compared to samples taken before the treatment started. While amoxicillin and clindamycin decreased the proportion of beneficial gut microbes relative to harmful ones, lolamicin had little effect on the bacterial ecosystem.
Finally, the researchers looked at whether lolamicin would affect the body’s ability to clear C. difficile, a microbe that can proliferate following treatment with some antibiotics and cause secondary bacterial infections. Given that lolamicin didn’t impact the mouse microbiome in other experiments, the researchers anticipated that mice who were treated with it would be able to get rid of C. difficile without any issues.
Their hypothesis proved correct: While C. difficile colonized at high levels in the guts of mice that were treated with amoxicillin or clindamycin, mice that received lolamicin had very little C. difficile growth.
Though the results are a positive sign, it will be years before lolamicin or drugs like it are ready for prime time, the scientists noted in the press release. They still need to find ways to reduce the risk of resistance to it, either through tweaking the compound or combining it with other antibiotics. The compound’s journey to the market may also be hampered by the fact that despite the desperate need for new antibiotics, pharmas have have little financial incentive to make them.
That said, “the minimal perturbation of the gut microbiome by lolamicin highlights this doubly selective strategy as promising for developing microbiome-sparing antibiotics against [g]ram-negative pathogens,” the researchers wrote in their paper. They believe it might also be effective against P. aeruginosa or A. baumannii, two other multidrug-resistant pathogens that plague hospitals.
“Pathogen-specific antibiotics such as lolamicin will be critical to minimizing collateral damage to the gut microbiome,” the researchers concluded in their paper. “This microbiome-sparing effect would make such antibiotics superior for patients compared with antibiotics in current clinical practice.”