Reverse Fosfomycin Resistance

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Overview 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. With few new drugs are in the pipeline, fosfomycin – which was discovered over four decades ago – has drawn renewed interest as an agent against drug-resistant bacteria. Although fosfomycin is currently effective against 90 percent of tested pathogens, it’s no silver bullet, and increased use will only lead to increased resistance. To disarm bacterial defenses against fosfomycin, researchers at the University of Pittsburgh have discovered a compound called ANY1 that selectively blocks the mechanism by which bacteria resist treatment. When applied together with ANY1, fosfomycin is once again effective against formerly resistant bacteria. This cocktail presents a new opportunity to fight back against “superbugs” – tenacious bacterial infections that evade all known current treatments.   Fosfomycin-resistant gram-negative bacteria include Klebsiella pneumoniae, Escherichia coli, Enterobacter cloacae, and Pseudomonas aeruginosa, each of which also takes a multidrug-resistant form. These bacteria mount resistance by deploying fosfomycin-modifying enzymes, most frequently FosA. ANY1 restores fosfomycin sensitivity by competitively inhibiting FosA. A cocktail containing ANY1 and fosfomycin significantly reduced the concentration of fosfomycin-resistant K. pneumoniae, E. coli, E. cloacae, and P. aeruginosa cultures. 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. Using ANY1 to restore fosfomycin sensitivity is similar to the widespread use of β-lactamase inhibitors to restore the function of β-lactam antibiotics – such as penicillin – but currently ANY1 is the only agent with a demonstrated capacity to restore the efficacy of fosfomycin.   Advantages ANY1 is the only agent that is demonstrated to reverse fosfomycin resistance in bacteria Postpones the need to develop brand new antibiotics Potent at low concentrations   Applications Treating multidrug-resistant bacterial infections, such as carbapenem-resistant Enterobacteriaceae Treating known fosfomycin-resistant bacterial infections Future research involving the inhibition of FosA   Stage of Development Tested in vitro   IP Status Provisional patent filed