New drug candidate can fight more than 200 antibiotic-resistant bacteria

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  • Researchers have modified an existing antibiotic to create a new molecule that may be effective against drug-resistant Gram-negative bacteria.
  • A molecule synthesized by the researchers, fabimycin, has shown promise in combating more than 200 mostly harmless drug-resistant bacteria that are commonly present in the human gut microbiome.
  • Fabimycin has also shown efficacy against Gram-negative bacteria in mouse infection models of difficult urinary tract infection (UTI) and acute pneumonia.
  • The results suggest that fabimycin could possibly be used to treat Gram-negative infections in humans.

Bacterial resistance to antimicrobials (AMR) occurs when bacteria mutate over time and no longer respond to antibiotics, making infections harder to treat and increasing the risk of disease spread, serious illness and death. Scientists have described infections due to antibiotic-resistant bacteria as being a threat to modern healthcare.

Bacteria can be classified as Gram-positive or Gram-negative based on the structure of their cell membranes.

In 1884, a Danish bacteriologist named Hans Christian Gram developed a test to differentiate bacteria based on the chemical and physical composition of their cell walls. Gram discovered that some bacteria had a thin cell wall of peptidoglycan, in addition to a dense outer membrane and efflux pumps. These bacteria have been classified as Gram-negative and their cellular structure prevents antibiotic molecules from entering and accumulating in the cell. In comparison, Gram-positive bacteria have no outer layer, but are surrounded by thick layers of mesh-like peptidoglycan.

Due to the structural difference of the cells, Gram-negative bacteria, such as pneumonia, urinary tract infections (UTI), and bloodstream infections are more difficult to treat than those caused by Gram-positive bacteria.

In 2017, the World Health Organization (WHO) identified a list of priority antibiotic resistant pathogens which pose a “great threat to human health”. The agency stressed the urgency of the need for new antibiotics. The majority of pathogens listed by the WHO are Gram-negative bacteria.

Gram-negative bacteria also include four of the six deadliest drug-resistant pathogens.

Dr. Paul J. Hergenrotherprofessor 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, responsible for catalyzing the rate-determining step in bacterial fatty acid biosynthesis. Prior to this study, the use of the FabI enzyme as an antibiotic target had only been taken advantage of in Gram-positive infections.

The results of this study can be found in AEC Core Sciences.

The researchers understood that the physico-chemical characteristics of small molecules have an impact on their ability to penetrate and accumulate inside Gram-negative bacterial cells. This emerging knowledge is captured in new guidelines for the design of penetrating Gram-negative compounds, known as .

Dr. Hergenrother’s team started with Debio-1452, a very potent FabI inhibitor against Gram-positive Staphylococcus aureus. Guided by the eNTRy rules, the researchers made structural modifications to the Debio-1452 molecule with the aim of creating a new molecule that retained the FabI inhibition power of Debio-1452 but also possessed activity against Gram-negative bacteria.

Among a suite of newly synthesized Debio-1452 drug candidates, one molecule – which the researchers coined fabimycin – showed superior potency in initial testing.

After identifying fabimycin as the most promising gram-negative antibiotic candidate, the researchers evaluated the antibacterial activity of fabimycin against a panel of multidrug-resistant gram-negative clinical isolates.

They found that fabimycin has impressive activity against over 200 clinical isolates of Escherichia coli, Klebsiella pneumoniaeand Acinetobacter baumannii.

Fabimycin also exhibited a narrow range of minimum inhibitory concentrations (MICs) among all clinical isolates Fabimycin also exhibited a low and narrow range of minimum inhibitory concentrations (MICs) compared to other clinical isolates tested. The 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 widespread in existing bacterial populations.”

In addition, fabimycin demonstrated high specificity for pathogenic bacteria compared to commensal bacteria (normal microflora). The researchers attribute this to the fact that commensal bacteria may not be dependent on the FabI enzyme and would therefore be insensitive to FabI enzyme inhibition by fabimycin.

This finding suggests that fabimycin may 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 difficult and drug-resistant strain of Escherichia coli. This bacteriumm causes the vast majority of urinary tract infections.

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 new class of antibiotics approved by the FDA for the treatment of gram-negative pathogens” in more than half a century, putting the discovery of fabimycin in perspective.

Fabimycin’s high potency against Gram-negative clinical isolates, low frequency of bacterial resistance, and efficacy in mouse models of infection 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 can 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 translate into an effective treatment for persistent Gram-negative infections. However, he pointed out that “significant financial investments [is needed] to get there, and historically it has been difficult in the field of antibiotics.

“We urgently need new antibiotics that target novel bacterial processes, and work by the Hergenrother group identifies one such compound,” Dr Wuest said. “Their results are very exciting and have the potential to make it to the clinic with the right financial support from the community.”

When asked how this research would progress, Dr. Hergenrother replied NTM,”The next step is to work with a suitable commercial partner on IND enabling studies as part of advancing this technology to the clinic.

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