200+ antibiotic-resistant bacteria may be treated using a new drug candidate

By SNEHA MAVIS.

Bacterial antimicrobial resistance (AMR) develops when bacteria evolve over time and stop responding to antibiotics, making infections harder to control and raising the risk of disease spread, severe sickness, and death. Infections caused by antibiotic-resistant bacteria have been identified as a threat to current healthcare by scientists. 

Based on the composition of their cell membranes, bacteria can be classified as Gram-positive or Gram-negative. Gram-negative bacteria, such as pneumonia, UTI, and septicemia, are more difficult to cure than Gram-positive bacteria because of the difference in cell structure.

The World Health Organization (WHO) issued a list of antibiotic-resistant prioritized microbes in 2017 that pose a "great threat to human health." New antibiotics are urgently needed, the organization emphasized. Gram-negative bacteria account for the majority of pathogens identified by the WHO. Four of the six most fatal drug-resistant pathogens are also Gram-negative bacteria. 

Dr. Paul J. Hergenrother, a chemistry professor at the University of Illinois, and his team set out to develop an antibiotic that would accumulate in Gram-negative cells. Dr. Hergenrother and his team made the decision to focus on the FabI enzyme, which is in charge of catalyzing the rate-determining step in bacterial biosynthesis of fatty acids. This study's findings have been published in ACS Central Science.

Fabimycin:

Debio-1452, a powerful FabI inhibitor against Gram-positive Staphylococcus aureus, served as the starting point for Dr. Hergenrother's team. The researchers used the eNTRy guidelines to make structural changes to the Debio-1452 molecule to create a new compound that kept the FabI inhibitory potency of Debio-1452 but also had activity toward Gram-negative bacteria. One molecule, called Fabimycin by the researchers, stood out in initial tests among a set of recently synthesized Debio-1452 drug candidates.

The researchers evaluated the antibacterial efficacy of Fabimycin vs a group of multidrug-resistant Gram-negative clinical strains after identifying it as the most potential Gram-negative antibiotic candidate. They discovered that Fabimycin exhibits remarkable effectiveness against more than 200 clinical strains of Acinetobacter baumannii, Klebsiella pneumonia, and Escherichia coli. The minimum inhibitory concentrations (MICs) for fabimycin were also low and narrow compared to the other clinical isolates examined.

Fabimycin in mouse models: 

After determining an appropriate Fabimycin dose in mice, the researchers tested Fabimycin's efficacy in mice infected with a difficult, drug-resistant variant of Escherichia coli. Most UTIs are brought on by this bacterium. The quantity of drug-resistant bacterium in the spleen, bladder, liver, and renal tissues of mice was lowered to pre-infection levels or below by giving them fabimycin intravenously 3 times per day.