Combating Fosfomycin Resistance in Gram-positive Pathogens

Friday March 25th, 2022 in Hand 1144

Abstract: The treatment of bacterial infections is compromised by the spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR) pathogens. New strategies to combat resistant as well as emerging bacteria are urgently needed to limit further development of antimicrobial resistance. Combining currently approved antibiotics with resistance neutralizing agents is a promising direction. The overall goal of our research is to develop effective front-line antimicrobial strategies from an approved, safe, and broad-spectrum antibiotic so newer antimicrobials, as well as final-option drugs, can be held in reserve to minimize emerging resistance. Fosfomycin is effective against both Gram-negative and Gram-positive pathogens and represents a promising candidate for developing a front-line agent. Moreover, fosfomycin as a combination therapy is currently in Phase III clinical trials for inhalation in patients with bacterial infections associated with cystic fibrosis (CF). Primary resistance to fosfomycin arises from fosfomycin-modifying enzymes of the Vicinal Oxygen Chelate (VOC) superfamily. The role of VOC enzymes is to detoxify endogenous and xenobiotic compounds. FosB is the principal fosfomycin-modifying enzyme of methicillin-resistant Staphylococcus aureus (MRSA). It is a Mn2+-dependent thiol transferase that covalently attaches bacillithiol (BSH) to fosfomycin, inactivating the antibiotic. fosb knockout strains of MRSA demonstrate significantly increased susceptibility to fosfomycin with an experimentally determined minimum inhibitory concentration (MIC) of 0.5 mg/mL, identifying suppression of the enzyme as a viable therapeutic strategy. We combine X-ray structural data with virtual inhibitor screening to identify small molecules that serve as FosB inhibitors and lower the MIC of fosfomycin in MRSA so that it can be used as an effective treatment.

Bio: Matthew received his Bachelor’s degrees in Chemistry and Geology at Eastern Kentucky University and his Ph.D. degree at North Carolina State University working with Stefan Franzen on spectroscopy of heme peroxidases. Matthew was then an NIH Postdoctoral Fellow in the lab of Richard Armstrong at Vanderbilt University Medical Center, where he studied thiol transferases. He then did a second postdoc at VUMC with Walter Chazin, where he investigated the electron transfer mechanism of human DNA Primase.  Matthew began his independent career at the University of Alabama in 2017.

Please join us for a reception with Dr. Thompson at 3:00 P.M. in Hand 1134.
Hosted by: Dr. Nick Fitzkee