Combating fosfomycin resistance in methicillin-resistant staphylococcus aureus
Ended Project Grant Awarded Last action
- Award ID
- R15GM148956
- Recipient
-
University Of Alabama UEI RCNJEHZ83EV6
- Awarding agency
-
National Institute of General Medical Sciences
National Institutes of Health, Department of Health and Human Services
- Obligated
- $859,028
Award facts
- Assistance listing
- 93.859 Biomedical Research and Research Training
- Completion date
- Originally
- Place of performance
- Tuscaloosa, AL 35487, USA
Award details come from USAspending.gov.
Description
- 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. Primary resistance to fosfomycin arises from fosfomycin-modifying enzymes of the vicinal oxygen chelate (VOC) superfamily. The primary role of VOC enzymes is to detoxify endogenous and xenobiotic compounds. Genes encoding VOC fosfomycin resistance enzymes have been identified in almost all of the most drug-resistant gram-negative and gram-positive pathogens and in mycobacteria. Fosb is the principal fosfomycin-modifying enzyme of methicillin-resistant staphylococcus aureus (mrsa). IT covalently attaches bacillithiol (BSH) to fosfomycin, inactivating the antibiotic. Fosb knockout strains of mrsa demonstrate significantly increased susceptibility to fosfomycin, identifying suppression of the enzyme as a potential therapeutic strategy. We hypothesize that combining x-RAY structural data of BSH-bound fosb with structure-based virtual inhibitor screening will identify small molecules that can serve as fosb inhibitors and lower the MIC of fosfomycin in mrsa, thereby making fosfomycin an effective treatment against mrsa. In aim 1, we will use structure-based virtual screening to identify new small molecule scaffolds that inhibit fosb and evaluate them with respect to kinetics and synergistic effectiveness when combined with fosfomycin. In addition, we will determine crystal structures of fosb with the new compounds to guide future medicinal chemistry approaches. In aim 2, we will determine a novel structure of fosb complexed with BSH. To date, none of the VOC fosfomycin resistance enzymes have been structurally characterized with respect to their native thiol, and a structure of fosb with BSH bound will be transformative to our understanding of the mechanism of VOC- catalyzed fosfomycin resistance. The BSH-bound structure will then be used as a starting model for additional structure-based virtual screening. This research will involve undergraduate students in meaningful projects that expose them to a wide range of techniques and help develop their critical thinking, research skills, and interest in biomedical careers.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $0 | |
| Amendment | $429,514 | |
| Original award | $429,514 |
Quick answers
Who received award R15GM148956?
R15GM148956 was awarded to University Of Alabama by National Institute of General Medical Sciences (National Institutes of Health) on September 15, 2022.
How much is award R15GM148956 worth?
$859,028 has been obligated on R15GM148956.
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