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Featured Structure: KDOP synthases from Burkholderia

The Seattle Structural Genomics Center for Infectious Disease (SSGCID) has solved three new structures for a promising antibacterial drug target, bacterial KDOP synthase (aka 3-deoxy-D-manno-2-octulosonate-8-phosphate synthase), from three Burkholderia species. Burkholderia are Gram-negative bacteria that cause extremely infectious, life threatening infections; including melioidosis, an often fatal disease, and severe lung infections in children with cystic fibrosis. The severity of Burkholderia infections are frequently due to increasing antibiotic resistance.

KDOP synthases perform an essential step in Gram-negative bacterial outer membrane synthesis, are required for bacterial life and are not found in humans. Researchers believe an inhibitor of KDOP synthase would kill Burkholderia and other Gram-negative bacteria. The structures SSGCID has solved will facilitate structure-based drug development, a process in which the 3-D structure is used to guide drug design, in this case an antibiotic that is effective against Burkholderia and other Gram-negative bacteria.

SSGCID solved KDOP synthetase structures for three different Burkholderia bacterial species:

  • Burkholderia cenocepacia
  • Burkholderia ambifaria: the Burkholderia species that most commonly infect children with cystic fibrosis (PDB.org: 3TML and PDB: 3T4C)
  • Burkholderia pseudomallei: the Burkholderia species that causes melioidosis (PDB.org: 3SZ8, 3UND, and 3TMQ)

These KDOP synthetase structures have a high degree of structural similarity. One antibiotic drug could possibly inhibit all of the Burkholderia bacteria. In fact, since KDOP synthases are similar in all Gram-negative bacteria, it is very likely that a KDOP inhibitor could be an effective antibiotic for all Gram-negative bacteria.

Substrate-bound crystal structure of 2-dehydro-3-deoxyphosphooctonate aldolase from Burkholderia pseudomallei

Reference


Combining Functional and Structural Genomics to Sample the Druggable Bacterial Structome. Baugh, L., Gallagher, L.A., Patrapuvich, R., Clifton, M., Gardberg, A.S., Edwards, T.E., Armour, B., Begley, D.W., Dieterich, S.H., Dranow, D.M., Abendroth, J., Fairman, J.W., Foxx, D.III, Staker, B.L., Phan, I., Gillespie, A., Choi, R., Nakazawa-Hewitt, S., Nguyen, M.T., Napuli, A., Barrett, L., Buchko, G.W., Stacy, R., Myler, P.J., Stewart, L.J., Manoil, C., and Van Voorhis, W.C. PLoS One (2012) 8(1):e53851. PMID: 23382856..

Last Updated May 30, 2013

Last Reviewed May 30, 2013