4H3C

Structure of E. coli undecaprenyl diphosphate synthase in complex with BPH-987

Summary for 4H3C

• Entry DOI: 10.2210/pdb4h3c/pdb
• Related: 4H2J 4H2M 4H2O 4H38 4H3A
• Descriptor: Undecaprenyl pyrophosphate synthase, (2Z)-4-[3-(decyloxy)phenyl]-2-hydroxy-4-oxobut-2-enoic acid (3 entities in total)
• Functional Keywords: prenyl transferase inhibitor complex, alpha-helix, prenyl transferase, cell wall biosynthesis, farnesyl diphosphate binding, isopentenyl diphosphate binding, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Escherichia coli
• Total number of polymer chains: 2
• Total formula weight: 58007.55

Authors

Zhu, W.,Oldfield, E. (deposition date: 2012-09-13, release date: 2012-12-19, Last modification date: 2023-09-20)

Primary citation

Zhu, W.,Zhang, Y.,Sinko, W.,Hensler, M.E.,Olson, J.,Molohon, K.J.,Lindert, S.,Cao, R.,Li, K.,Wang, K.,Wang, Y.,Liu, Y.L.,Sankovsky, A.,de Oliveira, C.A.,Mitchell, D.A.,Nizet, V.,McCammon, J.A.,Oldfield, E.
Antibacterial drug leads targeting isoprenoid biosynthesis.
Proc.Natl.Acad.Sci.USA, 110:123-128, 2013

PubMed Abstract: With the rise in resistance to antibiotics such as methicillin, there is a need for new drugs. We report here the discovery and X-ray crystallographic structures of 10 chemically diverse compounds (benzoic, diketo, and phosphonic acids, as well as a bisamidine and a bisamine) that inhibit bacterial undecaprenyl diphosphate synthase, an essential enzyme involved in cell wall biosynthesis. The inhibitors bind to one or more of the four undecaprenyl diphosphate synthase inhibitor binding sites identified previously, with the most active leads binding to site 4, outside the catalytic center. The most potent leads are active against Staphylococcus aureus [minimal inhibitory concentration (MIC)(90) ∼0.25 µg/mL], and one potently synergizes with methicillin (fractional inhibitory concentration index = 0.25) and is protective in a mouse infection model. These results provide numerous leads for antibacterial development and open up the possibility of restoring sensitivity to drugs such as methicillin, using combination therapies.

PubMed: 23248302
DOI: 10.1073/pnas.1219899110

Experimental method

X-RAY DIFFRACTION (1.93 Å)