New antibiotic molecule kills dozens of the toughest types of superbugs

Good news! Maybe it is time to dial down the alarmism and hysteria about antimicrobial resistance! Human ingenuity can handle it!

What stands out here, is the approach taken by the researchers. They started with an antibiotic against gram-positive bacteria and deliberately modified it to treat gram-negative bacteria.

"Scientists on the new study have now developed a novel antibiotic candidate that shows promise. The team started with an existing antibiotic that’s effective against gram-positive bacteria, and adapted it with a series of structural modifications to try to make it stronger against gram-negative strains.
One of the modified compounds in particular stood out. Named fabimycin, the drug candidate worked well against more than 200 clinically isolated colonies of antibiotic-resistant bacteria, comprising a total of 54 strains of bugs like E. coli, Klebsiella pneumoniae and Acinetobacter baumannii. In tests in mice, fabimycin was found to clear up drug-resistant cases of pneumonia or urinary tract infections, reducing the bacteria levels even lower than they were pre-infection.
Importantly, fabimycin was relatively selective in its attack, leaving some types of harmless bacteria intact. ..."

"... The team started with an antibiotic that was active against gram-positive bacteria and made a series of structural modifications that they believed would allow it to act against gram-negative strains. One of the modified compounds, dubbed fabimycin, proved potent against more than 300 drug-resistant clinical isolates, while remaining relatively inactive toward certain gram-positive pathogens and some typically harmless bacteria that live in or on the human body. In addition, the new molecule reduced the amount of drug-resistant bacteria in mice with pneumonia or urinary tract infections to pre-infection levels or below, performing as well as or better than existing antibiotics at similar doses. ..."

From the abstract:

"Genomic studies and experiments with permeability-deficient strains have revealed a variety of biological targets that can be engaged to kill Gram-negative bacteria. However, the formidable outer membrane and promiscuous efflux pumps of these pathogens prevent many candidate antibiotics from reaching these targets. One such promising target is the enzyme FabI, which catalyzes the rate-determining step in bacterial fatty acid biosynthesis. Notably, FabI inhibitors have advanced to clinical trials for Staphylococcus aureus infections but not for infections caused by Gram-negative bacteria. Here, we synthesize a suite of FabI inhibitors whose structures fit permeation rules for Gram-negative bacteria and leverage activity against a challenging panel of Gram-negative clinical isolates as a filter for advancement. The compound to emerge, called fabimycin, has impressive activity against >200 clinical isolates of Escherichia coli, Klebsiella pneumoniae, and Acinetobacter baumannii, and does not kill commensal bacteria. X-ray structures of fabimycin in complex with FabI provide molecular insights into the inhibition. Fabimycin demonstrates activity in multiple mouse models of infection caused by Gram-negative bacteria, including a challenging urinary tract infection model. Fabimycin has translational promise, and its discovery provides additional evidence that antibiotics can be systematically modified to accumulate in Gram-negative bacteria and kill these problematic pathogens."

New antibiotic molecule kills dozens of the toughest types of superbugs

New drug candidate fights off more than 300 drug-resistant bacteria

An Iterative Approach Guides Discovery of the FabI Inhibitor Fabimycin, a Late-Stage Antibiotic Candidate with In Vivo Efficacy against Drug-Resistant Gram-Negative Infections (open access)

Table 1. Spectrum of Fabimycin Activity