PDBsum entry 6mo4

Hydrolase/inhibitor

PDB id: 6mo4

Contents

Protein chain

299 a.a.

Ligands

JWM

Metals

_MG

Waters ×157

PDB id:

6mo4

Name:

Hydrolase/inhibitor

Title:

Co-crystal structure of p. Aeruginosa lpxc-50067 complex

Structure:

Udp-3-o-acyl-n-acetylglucosamine deacetylase. Chain: a. Synonym: udp-3-o-acyl-glcnac deacetylase,udp-3-o-[r-3- hydroxymyristoyl]-n-acetylglucosamine deacetylase. Engineered: yes

Source:

Pseudomonas aeruginosa pao1. Organism_taxid: 208964. Strain: atcc 15692 / dsm 22644 / cip 104116 / jcm 14847 / lmg 12228 / 1c / prs 101 / pao1. Gene: lpxc, enva, pa4406. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

1.84Å R-factor: 0.180 R-free: 0.226

Authors:

A.J.Stein,Z.Assar,M.C.Holt,F.Cohen,L.Andrews,R.Cirz

Key ref:

F.Cohen et al. (2019). Optimization of LpxC Inhibitors for Antibacterial Activity and Cardiovascular Safety. ChemMedChem, 14, 1560-1572. PubMed id: 31283109 DOI: 10.1002/cmdc.201900287

Date:

04-Oct-18 Release date: 17-Jul-19

Protein chain

P47205  (LPXC_PSEAE) -  UDP-3-O-acyl-N-acetylglucosamine deacetylase from Pseudomonas aeruginosa (strain ATCC 15692 / DSM 22644 / CIP 104116 / JCM 14847 / LMG 12228 / 1C / PRS 101 / PAO1)

Seq: 303 a.a.

Struc: 299 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: E.C.3.5.1.108 - UDP-3-O-acyl-N-acetylglucosamine deacetylase.
• Reaction: a UDP-3-O-[(3R)-3-hydroxyacyl]-N-acetyl-alpha-D-glucosamine + H2O = a UDP-3-O-[(3R)-3-hydroxyacyl]-alpha-D-glucosamine + acetate
• Cofactor: Zn(2+)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Key reference

DOI no: 10.1002/cmdc.201900287

ChemMedChem 14:1560-1572 (2019)

PubMed id: 31283109

Optimization of LpxC Inhibitors for Antibacterial Activity and Cardiovascular Safety.

F.Cohen, J.B.Aggen, L.D.Andrews, Z.Assar, J.Boggs, T.Choi, P.Dozzo, A.N.Easterday, C.M.Haglund, D.J.Hildebrandt, M.C.Holt, K.Joly, A.Jubb, Z.Kamal, T.R.Kane, A.W.Konradi, K.M.Krause, M.S.Linsell, T.D.Machajewski, O.Miroshnikova, H.E.Moser, V.Nieto, T.Phan, C.Plato, A.W.Serio, J.Seroogy, A.Shakhmin, A.J.Stein, A.D.Sun, S.Sviridov, Z.Wang, K.Wlasichuk, W.Yang, X.Zhou, H.Zhu, R.T.Cirz.

ABSTRACT

UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) is a Zn²⁺ deacetylase that is essential for the survival of most pathogenic Gram-negative bacteria. ACHN-975 (N-((S)-3-amino-1-(hydroxyamino)-3-methyl-1-oxobutan-2-yl)-4-(((1R,2R)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)benzamide) was the first LpxC inhibitor to reach human clinical testing and was discovered to have a dose-limiting cardiovascular toxicity of transient hypotension without compensatory tachycardia. Herein we report the effort beyond ACHN-975 to discover LpxC inhibitors optimized for enzyme potency, antibacterial activity, pharmacokinetics, and cardiovascular safety. Based on its overall profile, compound 26 (LPXC-516, (S)-N-(2-(hydroxyamino)-1-(3-methoxy-1,1-dioxidothietan-3-yl)-2-oxoethyl)-4-(6-hydroxyhexa-1,3-diyn-1-yl)benzamide) was chosen for further development. A phosphate prodrug of 26 was developed that provided a solubility of >30 mg mL^-1 for parenteral administration and conversion into the active drug with a t_1/2 of approximately two minutes. Unexpectedly, and despite our optimization efforts, the prodrug of 26 still possesses a therapeutic window insufficient to support further clinical development.