Folate is an essential vitamin that is a critical precursor for the biosynthesis of purines, pyrimidines, and amino acids. The importance of folate makes folate biosynthesis pathway a key target for antimicrobial therapy. Creative Biolabs has developed a top drug discovery platform to determine the mode of action of antibacterial drug targets in folate biosynthesis pathway.
Prokaryotic and lower eukaryotic microorganisms synthesize folate in the cells by the support of several enzymes. However, higher eukaryotes including mammals do not synthesize folate and do not possess these kinds of enzymes. They directly derive folate from their diet. Consequently, the enzymes of the de novo folate synthesis pathway provide ideal targets for therapeutic intervention for treatment of infections caused by prokaryotic and lower eukaryotic pathogens. The folate biosynthesis pathway comprises six committed enzymes: GTPCH, NUDIX pyrophosphatase, DHNA, HPPK, DHPS and DHFS, and they can be potential targets for novel antibiotics.
Figure 1. The folate biosynthetic pathway. (Swarbrick et al. 2008)
Formation of HP-DHNA
DHNA catalyzes both the epimerization of 7,8-dihydroneopterin (DHNP) to 7,8-dihydromonapterin (DHMP) and the conversion of DHNP or DHMP to 6-hydroxymetyl-7,8-dihydropterin (HP). Some inhibitors of DHNA were dihydropterins closely related to substrate and product structures.
Pyrophosphoryl Transfer-HPPK
HPPK catalyzes the transfer of pyrophosphate from a bound ATP to 6-hydroxymethyl-7,8-dihydropterin (HP). The currently determined HPPK structures have high sequence identity and active site structural similarity, which suggests that HPPK can be developed to broad spectrum anti-infective targets.
Old Target with New Potential-DHPS
DHPS catalyzes the conversion of 6-hydroxymethyl-7,8-dihydropterin-pyrophosphate (DHPP) and pABA to 7,8-dihydropteroate. It is the target of “sulfadrug” class of drugs that act as competitive inhibitors and dead end substrate analogs of pABA. However, recently, the resistance and toxicities associated with sulfonamides have led to decrease use in clinical. The structures of DHPS include holoenzymes and binary complexes with pterin substrate. Compounds that bind to the pterin binding site of DHPS are anticipated by bypass sulfonamide resistance. By virtual screening, synthetic and structural studies, Creative Biolabs will identify novel inhibitors and map the pterin binding pocket.
Addition of Glutamates-DHFS
Dihydrofolate synthase (DHFS) catalyzes the final step in the folate synthesis pathway: addition of glutamate to dihydropteroate. As DHFS activity is essential for bacteria and absent in humans, DHFS has the potential to be a target for selective inhibitors. However, targeting DHFS is complicated as it shares a high degree of similarity with folylpolyglutamate synthase (FPGS) which is found in all organisms. Therefore, in the design of inhibitors for DHFS, we also consider their effect on FPGS.
Creative Biolabs' professional group has the ability to identify antibacterial drug targets in folate biosynthesis pathway. For more detailed information, please feel free to contact us or directly sent us an inquiry.
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