9CSI

A. baumannii MsbA Bound to Cerastecin Compound 5

This is a non-PDB format compatible entry.

Summary for 9CSI

• Entry DOI: 10.2210/pdb9csi/pdb
• Descriptor: Lipid A export ATP-binding/permease protein MsbA, PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER, MONOVACCENIN, ... (6 entities in total)
• Functional Keywords: msba, antibacterial, inhibitor, cerastecin, antibiotic
• Biological source: Acinetobacter baumannii
• Total number of polymer chains: 1
• Total formula weight: 68559.51

Authors

Klein, D.J.,Ishchenko, A.,Soisson, S.,Cheng, R.,Hennig, M. (deposition date: 2024-07-23, release date: 2024-09-04, Last modification date: 2024-10-02)

Primary citation

Skudlarek, J.W.,Cooke, A.J.,Mitchell, H.J.,Babaoglu, K.,Shaw, A.W.,Tong, L.,Nomland, A.B.,Labroli, M.,Sha, D.,Mulhearn, J.J.,Wu, C.,Li, S.W.,Beshore, D.C.,Hughes, J.M.E.,Jouffroy, M.,Wang, H.,Balibar, C.J.,Painter, R.E.,Shen, P.,Lange, H.S.,Ishchenko, A.,Chen, Y.T.,Klein, D.J.,Tracy, R.W.,Miller, R.R.,Cabalu, T.D.,Wu, Z.,Leithead, A.,Scapin, G.,Hruza, A.W.,Dzhekieva, L.,Bukhtiyarova, M.,Homsher, M.F.,Xu, M.,Bahnck-Teets, C.,McKenney, D.,Buevich, A.V.,Liu, J.,Zhang, L.K.,Meng, T.,Kelly, T.,DiNunzio, E.,Soisson, S.,Cheng, R.K.Y.,Hennig, M.,Raheem, I.,Walker, S.S.
Cerastecin Inhibition of the Lipooligosaccharide Transporter MsbA to Combat Acinetobacter baumannii : From Screening Impurity to In Vivo Efficacy.
J.Med.Chem., 67:15620-15675, 2024

PubMed Abstract: , a commonly multidrug-resistant Gram-negative bacterium responsible for large numbers of bloodstream and lung infections worldwide, is increasingly difficult to treat and constitutes a growing threat to human health. Structurally novel antibacterial chemical matter that can evade existing resistance mechanisms is essential for addressing this critical medical need. Herein, we describe our efforts to inhibit the essential lipooligosaccharide (LOS) ATP-binding cassette (ABC) transporter MsbA. An unexpected impurity from a phenotypic screening was optimized as a series of dimeric compounds, culminating with (cerastecin D), which exhibited antibacterial activity in the presence of human serum and a pharmacokinetic profile sufficient to achieve efficacy against in murine septicemia and lung infection models.

PubMed: 39172133
DOI: 10.1021/acs.jmedchem.4c01277

Experimental method

X-RAY DIFFRACTION (2.8 Å)