4OON: Crystal Structure Of Pbp1a In Complex With Compound 17 ((4z,8s,11e, 14s)-5-(2-amino-1,3-thiazol-4-yl)-14-(5,6-dihydroxy-1,3-dioxo-1,3- Dihydro-2h-isoindol-2-yl)-8-formyl-2-methyl-6-oxo-3,10-dioxa-4,7,11- Triazatetradeca-4,11-diene-2,12,14-tricarboxylic Ac

Citation:
Abstract
Multidrug-resistant Gram-negative pathogens are an emerging threat to human health, and addressing this challenge will require development of new antibacterial agents. This can be achieved through an improved molecular understanding of drug-target interactions combined with enhanced delivery of these agents to the site of action. Herein we describe the first application of siderophore receptor-mediated drug uptake of lactivicin analogues as a strategy that enables the development of novel antibacterial agents against clinically relevant Gram-negative bacteria. We report the first crystal structures of several sideromimic conjugated compounds bound to penicillin binding proteins PBP3 and PBP1a from Pseudomonas aeruginosa and characterize the reactivity of lactivicin and beta-lactam core structures. Results from drug sensitivity studies with beta-lactamase enzymes are presented, as well as a structure-based hypothesis to reduce susceptibility to this enzyme class. Finally, mechanistic studies demonstrating that sideromimic modification alters the drug uptake process are discussed.
PDB ID: 4OONDownload
MMDB ID: 119608
PDB Deposition Date: 2014/2/3
Updated in MMDB: 2014/05
Experimental Method:
x-ray diffraction
Resolution: 3.2  Å
Source Organism:
Similar Structures:
Biological Unit for 4OON: monomeric; determined by author and by software (PISA)
Molecular Components in 4OON
Label Count Molecule
Protein (1 molecule)
1
Penicillin-binding Protein 1A(Gene symbol: ponA)
Molecule annotation
Chemical (1 molecule)
1
1
* Click molecule labels to explore molecular sequence information.

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