Computer modeling has been used to create dual-action compounds with exciting potential as new antibiotics.
The proof-of-principle experiment raises the possibility of new antibiotics that can target harmful bacteria on two fronts and are therefore less likely to be defeated by resistant strains.
The collaboration between the University of Leeds and the John Innes Center has modeled potential new drugs based on the activity of thiophene compounds. These had previously shown promise as antibiotics before toxicity concerns prevented them from moving forward with human clinical trials.
By observing the activity of thiophenes, the team modeled new antibiotic candidates by computer, then synthesized and tested them on pathogenic bacteria Escherichia coli (E. coli).
They found that a series of biphenyl compounds inhibited the activity of harmful bacteria by targeting two enzymes, DNA gyrase and DNA topoisomerase IV, both essential for bacterial survival.
“These new compounds represent the start of a program that could lead to a new series of antibiotics,” said Professor Tony Maxwell, of the John Innes Centre, and one of the study’s authors.
“The current program represents proof of principle, and this initial success suggests that we will be able to discover even better antibiotic candidates in the future.” added the study’s first author, University of Leeds researcher Dr Kyle Orritt.
Researchers have previously discussed the implications of working with pharmaceutical companies, raising the possibility of a new source of antibiotics.
This work follows the discovery of a new opportunity to exploit the established antibacterial target DNA gyrase that offers a novel medicinal chemistry strategy.
New antibiotics are urgently needed due to the evolution of bacteria resistant to existing treatments. This problem of antimicrobial resistance (AMR) poses a huge threat to human health due to the increase in the number of incurable bacterial infections.
By 2050, AMR is predicted to be responsible for 10 million deaths worldwide each year, more deaths than cancer and costing the global economy $100 trillion.
De novo design of type II topoisomerase inhibitors as potential antimicrobial agents targeting a novel binding region, can be found in RSC Medical Chemistry https://pubs.rsc.org/en/content/articlelanding/2022 /md/d2md00049k