The results of this study appear in ACS Central Science.
Bacterial antimicrobial resistance (AMR) occurs when bacteria mutate over time and no longer respond to antibiotics, making infections more difficult to treat and increasing the risk of disease spread, severe illness, and death. Scientists have described infections due to antibiotic-resistant bacteria as a threat to modern healthcare.
Bacteria can be categorized as Gram-positive or Gram-negative based on the structure of their cell membranes.
Due to the cell structural difference, Gram-negative bacteria, such as pneumonia, urinary tract infections (UTI), and bloodstream infections, are harder to treat compared to those caused by Gram-positive bacteria.
In 2017, the World Health Organization (WHO) identified a list of antibiotic-resistant priority pathogens that present a “great threat to human health.” The agency highlighted the urgency of the need for new antibiotics. A majority of the pathogens listed by the WHO are Gram-negative bacteria.
Gram-negative bacteria also include four out of the six most lethal drug-resistant pathogens.
Dr. Paul J. Hergenrother, professor of chemistry at the University of Illinois, and his team of researchers, sought to create an antibiotic that would successfully accumulate in Gram-negative cells. Dr. Hergenrother and his team decided to target the FabI enzyme, which is responsible for catalyzing the rate-determining step in bacterial fatty acid biosynthesis. Before this study, the use of the FabI enzyme as an antibiotic target had only been leveraged in Gram-positive infections.
Researchers have come to understand that the physicochemical traits of small molecules impact their ability to penetrate and accumulate inside Gram-negative bacterial cells. This emerging knowledge is captured in new guidelines for the design of Gram-negative penetrant compounds.
Dr. Hergenrother’s team started with Debio-1452, a FabI inhibitor highly potent against Gram-positive Staphylococcus aureus. Guided by the entry rules, the researchers made structural modifications to the Debio-1452 molecule with the objective of creating a new molecule that retained the FabI inhibition potency of Debio-1452 but also possessed activity against Gram-negative bacteria.
Out of a suite of newly-synthesized Debio-1452 drug candidates, one molecule which the researchers coined fabimycin showed superior potency in initial tests. Having identified fabimycin as the most promising Gram-negative antibiotic candidate, the researchers assessed the antibacterial activity of fabimycin against a panel of multidrug-resistant Gram-negative clinical isolates. They found that fabimycin has impressive activity against more than 200 clinical isolates of Escherichia coli, Klebsiella pneumoniae, and Acinetobacter baumannii.
Fabimycin also exhibited a narrow range of minimum inhibitory concentrations (MICs) among all the clinical isolates Fabimycin also exhibited a low and narrow range of minimum inhibitory concentrations (MICs) compared to the other clinical isolates tested. MIC is the lowest concentration of an antibiotic that inhibits bacterial growth.
This result encouraged the authors “because it suggests that intrinsic resistance to fabimycin is not prevalent in existing bacterial populations.”
Furthermore, fabimycin demonstrated high specificity for pathogenic versus commensal bacteria (normal microflora). The researchers attribute this to the fact that commensal bacteria may not be reliant on the FabI enzyme and would thus be insensitive to FabI enzyme inhibition by fabimycin.
This discovery suggests that fabimycin could be less damaging to gut microflora than typical broad-spectrum antibiotics.
After establishing an effective dose of fabimycin in mice, the researchers evaluated the efficacy of fabimycin in mice infected with a challenging, drug-resistant strain of Escherichia coli. This bacterium causes the vast majority of UTIs. By administering fabimycin intravenously three times a day, the researchers were able to reduce the amount of drug-resistant bacteria in the spleen, bladder, liver, and kidney tissues of mice to pre-infection levels or below. In their paper, the researchers noted that there had not been a novel class of antibiotics FDA-approved for treatment of Gram-negative pathogens in more than half a century, putting the discovery of fabimycin into perspective.
The high potency of fabimycin against Gram-negative clinical isolates, low frequency of bacterial resistance, and efficacy in mouse infection models bode well for its efficacy in humans. The successful synthetic strategy presented in this study provides evidence that existing antibiotics effective against Gram-positive bacteria may be modified to penetrate and kill Gram-negative bacteria.
Dr. William M. Wuest, Georgia Research Alliance Distinguished Investigator and professor of chemistry at Emory University, expressed enthusiasm for the paper and its potential to be translated into an effective treatment for stubborn Gram-negative infections. However, he highlighted that “significant financial investment [is needed] to make it happen, and historically that has been challenging in the antibiotic field.”
“We are in dire need of new antibiotics that target new bacterial processes and the work by the Hergenrother group identifies one such compound,” said Dr. Wuest. “Their results are very exciting and have the potential to proceed to the clinic given the right financial support from the community.”
When asked how this research will progress, Dr. Hergenrother told MNT, the next step is to work with a suitable commercial partner on IND-enabling studies as part of advancing this technology to the clinic.