Nitric oxide inhibitors make antibiotics work more effectively. Image credit to Jeff Holden.
It happens repeatedly in science: Research in one area serendipitously is found to have potential applications in another area. In this week’s issue of the Proceedings of the National Academy of Sciences, investigators show that compounds originally developed to treat neurodegenerative disorders could be used to inhibit pathogenic bacteria.
Thomas Poulos’ group at the University of California, Irvine, have been collaborating with Richard Silverman’s group at Northwestern University to develop inhibitors for a protein called nitric oxide synthase, or NOS. These inhibitors were geared to act on NOS found in the mammalian central nervous system.
But in 2009, a paper by another group caught their attention. The authors of this paper had shown that nitric oxide, which is made by NOS, helped pathogenic bacteria resist antibiotics. “This suggested that inhibiting bacterial NOS might improve the killing efficacy of antibiotics,” says Poulos. “Since we had all these unique NOS inhibitors, we decided to test for the ability of these compounds to work synergistically with antibiotics.”
The investigators picked as a model organism Bacillus subtilis, which is much like the pathogenic methicillin-resistant Staphyloccocus aureus (better known as MRSA) and Bacillus anthracis, which causes antrax.
First, the investigators made sure that their NOS inhibitors could work alongside antibiotics to halt the growth of bacteria. Then they took the ones that worked and checked to see if the compounds would bind differently to the bacterial and mammalian versions of NOS. “We obviously want those that favor, or at least bind differently, to the bacterial enzyme,” notes Poulos.
The investigators narrowed their attention to two inhibitors. When bacteria were treated with each inhibitor and an antibiotic, they were killed more effectively than when treated with just an antibiotic. By comparing the crystal structures of the inhibitors bound to bacterial and mammalian NOS, the investigators found that these inhibitors targeted a region in the bacterial NOS that appeared to be particularly susceptible to these compounds.
This finding demonstrates that targeting bacterial NOS is one way to tackle pathogenic bacteria that may be growing more resistant to antibiotics.
But, in the meantime, Poulos says, the NOS inhibitors need to be made more selective. “We now know which region of the enzyme to target, so we ought to be able to develop compounds that selectively bind to bacterial NOS,” he says, adding that the team also needs to test its compounds in animal models.
Postscript: Research into antibiotic-resistant bacteria and new bacterial inhibitors always remind me of this classic song:
