We apologize for Proteopedia being slow to respond. For the past two years, a new implementation of Proteopedia has been being built. Soon, it will replace this 18-year old system. All existing content will be moved to the new system at a date that will be announced here.

8dtd

From Proteopedia

Jump to: navigation, search

Crystal Structure of FosB from Bacillus cereus with Zinc and Phosphonoformate

Structural highlights

8dtd is a 2 chain structure with sequence from Bacillus cereus ATCC 10987. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.95Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

FOSB_BACC1 Metallothiol transferase which confers resistance to fosfomycin by catalyzing the addition of a thiol cofactor to fosfomycin. L-cysteine is probably the physiological thiol donor (By similarity).

Publication Abstract from PubMed

The Gram-positive pathogen Staphylococcus aureus is a leading cause of antimicrobial resistance related deaths worldwide. Like many pathogens with multidrug-resistant strains, S. aureus contains enzymes that confer resistance through antibiotic modification(s). One such enzyme present in S. aureus is FosB, a Mn(2+)-dependent l-cysteine or bacillithiol (BSH) transferase that inactivates the antibiotic fosfomycin. fosB gene knockout experiments show that the minimum inhibitory concentration (MIC) of fosfomycin is significantly reduced when the FosB enzyme is not present. This suggests that inhibition of FosB could be an effective method to restore fosfomycin activity. We used high-throughput in silico-based screening to identify small-molecule analogues of fosfomycin that inhibited thiol transferase activity. Phosphonoformate (PPF) was a top hit from our approach. Herein, we have characterized PPF as a competitive inhibitor of FosB from S. aureus (FosB(Sa)) and Bacillus cereus (FosB(Bc)). In addition, we have determined a crystal structure of FosB(Bc) with PPF bound in the active site. Our results will be useful for future structure-based development of FosB inhibitors that can be delivered in combination with fosfomycin in order to increase the efficacy of this antibiotic.

Inhibition of Fosfomycin Resistance Protein FosB from Gram-Positive Pathogens by Phosphonoformate.,Travis S, Green KD, Gilbert NC, Tsodikov OV, Garneau-Tsodikova S, Thompson MK Biochemistry. 2023 Jan 3;62(1):109-117. doi: 10.1021/acs.biochem.2c00566. Epub , 2022 Dec 16. PMID:36525630^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Travis S, Green KD, Gilbert NC, Tsodikov OV, Garneau-Tsodikova S, Thompson MK. Inhibition of Fosfomycin Resistance Protein FosB from Gram-Positive Pathogens by Phosphonoformate. Biochemistry. 2023 Jan 3;62(1):109-117. PMID:36525630 doi:10.1021/acs.biochem.2c00566