Reversing Fosfomycin Resistance

Bacterial infections are increasingly resistant to the current arsenal of antibiotics, leading The Centers for Disease Control to declare multidrug resistant bacteria an urgent health threat. Few new drugs are in the pipeline, but fosfomycin – discovered over four decades ago – has drawn renewed interest for the treatment of urinary tract infections because it has a unique mechanism of action and no-cross resistance with other antibiotics. Fosfomycin is active against E. coli but exhibits reduced activity against many other gram-negative pathogens which chromosomally encode the fosA gene. FosA is a glutathione S-transferase that inactivates fosfomycin. Inhibition of FosA would expand the use of fosfomycin to all Gram-negative pathogens.

Description

Researchers at the University of Pittsburgh have discovered a compound called ANY1 that selectively blocks the mechanism by which bacteria resist fosfomycin treatment. When applied together with ANY1, fosfomycin is once again effective against formerly resistant bacteria. Bacteria mount resistance by deploying fosfomycin-modifying enzymes, most frequently FosA. ANY1 restores fosfomycin sensitivity in these pathogens by competitively inhibiting FosA. In control experiments, ANY1 did not have any impact on bacterial growth when applied alone, nor was it efficacious in conjunction with fosfomycin against a strain of E. coli that was engineered to lack the FosA gene. This cocktail presents the opportunity to fight back against so-called superbugs that evade all known current treatments.

Applications

· Treating multidrug-resistant bacterial infections, such as carbapenem-resistant Enterobacteriaceae
· Treating known fosfomycin-resistant bacterial infections
· Future research on inhibition of FosA

Advantages

· ANY1 is the only agent demonstrated to reverse fosfomycin resistance in bacteria
· Postpones the need to develop new antibiotics
· Potent even at low doses

Invention Readiness

In vitro data available

IP Status

https://patents.google.com/patent/WO2018132547A1

Related Publication(s)

Tomich, A. D., Klontz, E. H., Deredge, D., Barnard, J. P., McElheny, C. L., Eshbach, M. L., Weisz, O. A., Wintrode, P., Doi, Y., Sundberg, E. J., & Sluis-Cremer, N. (2019). Small-Molecule Inhibitor of FosA Expands Fosfomycin Activity to Multidrug-Resistant Gram-Negative Pathogens. Antimicrobial Agents and Chemotherapy, 63(3). https://doi.org/10.1128/aac.01524-18

Ito, R., Mustapha, M. M., Tomich, A. D., Callaghan, J. D., McElheny, C. L., Mettus, R. T., Shanks, R. M. Q., Sluis-Cremer, N., & Doi, Y. (2017). Widespread Fosfomycin Resistance in Gram-Negative Bacteria Attributable to the Chromosomal fosA Gene. mBio, 8(4). https://doi.org/10.1128/mbio.00749-17