A breakthrough compound destroys over 300 drug-resistant bacteria
- The new drug inhibits drug-resistant bacteria without harming helpful microbes.
- The compound infiltrates the defenses of gram-negative bacteria.
- It could one day be used to treat stubborn infections.
Medicine is constantly on the lookout for drugs that can kill drug-resistant bacteria. In February, researchers, led by Despoina Mavridou of The University of Texas, found a new way to reduce antibiotic resistance in bacteria that cause human diseases, such as E. coli, K. pneumoniae, and P. aeruginosa.
Treating difficult antibiotic-resistant infections
Then in May, researchers successfully used bacteriophages to treat an antibiotic-resistant mycobacterial lung infection. This process led the way for a young National Jewish Health patient with cystic fibrosis to receive a life-saving lung transplant.
Finally, in July, scientists from Rockefeller University synthesized a novel antibiotic with the help of computer models of bacterial gene products capable of killing even bacteria resistant to other antibiotics.
Now, researchers have reported a new molecule that inhibits drug-resistant bacteria in lab experiments, as well as in mice with pneumonia and urinary tract infections, according to a statement published in ACS Central Science on Wednesday. The researchers further note that this compound, called fabimycin, could one day be used to treat drug-resistant infections in humans as it has been reported to fight off more than 300 drug-resistant bacteria.
“Gram-negative bacteria are a class of microbes that infect millions of people worldwide, according to the U.S. Centers for Disease Control and Prevention, causing conditions such as pneumonia, urinary tract infections, and bloodstream infections. These bacteria are especially difficult to treat because they have strong defense systems – tough cell walls that keep most antibiotics out and pumps that efficiently remove those antibiotics that get inside. The microbes can also mutate to evade multiple drugs. Furthermore, treatments that do work aren’t very specific, eradicating many kinds of bacteria, including those that are beneficial,” wrote the researchers in their statement.
Infiltrating the defenses of gram-negative bacteria
Paul Hergenrother from the department of chemistry at Illinois University and his colleagues decided to engineer a drug that could infiltrate the defenses of gram-negative bacteria and treat infections without affecting other helpful microbes.
“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,” explained the researchers in their statement.
But that’s not all! The new molecule also decreased the amount of drug-resistant bacteria in mice with pneumonia or urinary tract infections to pre-infection levels or below. Essentially, it performed as well as or better than existing antibiotics at similar doses. These results indicate that fabimycin could one day be a promising treatment for stubborn difficult-to-tackle infections.
The new study is published in ACS Publications.
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.