8GK7
MsbA bound to cerastecin C
Summary for 8GK7
| Entry DOI | 10.2210/pdb8gk7/pdb |
| EMDB information | 40180 |
| Descriptor | Lipid A export ATP-binding/permease protein MsbA, PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER, 2-[(4-butylbenzene-1-sulfonyl)amino]-5-[(3-{4-[(4-butylbenzene-1-sulfonyl)amino]-3-carboxyanilino}-3-oxopropyl)carbamoyl]benzoic acid (3 entities in total) |
| Functional Keywords | msba, antibacterial, inhibitor, cerastecin, antimicrobial protein |
| Biological source | Acinetobacter baumannii |
| Total number of polymer chains | 2 |
| Total formula weight | 135578.44 |
| Authors | |
| Primary citation | Wang, H.,Ishchenko, A.,Skudlarek, J.,Shen, P.,Dzhekieva, L.,Painter, R.E.,Chen, Y.T.,Bukhtiyarova, M.,Leithead, A.,Tracy, R.,Babaoglu, K.,Bahnck-Teets, C.,Buevich, A.,Cabalu, T.D.,Labroli, M.,Lange, H.,Lei, Y.,Li, W.,Liu, J.,Mann, P.A.,Meng, T.,Mitchell, H.J.,Mulhearn, J.,Scapin, G.,Sha, D.,Shaw, A.W.,Si, Q.,Tong, L.,Wu, C.,Wu, Z.,Xiao, J.C.,Xu, M.,Zhang, L.K.,McKenney, D.,Miller, R.R.,Black, T.A.,Cooke, A.,Balibar, C.J.,Klein, D.J.,Raheem, I.,Walker, S.S. Cerastecins inhibit membrane lipooligosaccharide transport in drug-resistant Acinetobacter baumannii. Nat Microbiol, 9:1244-1255, 2024 Cited by PubMed Abstract: Carbapenem-resistant Acinetobacter baumannii infections have limited treatment options. Synthesis, transport and placement of lipopolysaccharide or lipooligosaccharide (LOS) in the outer membrane of Gram-negative bacteria are important for bacterial virulence and survival. Here we describe the cerastecins, inhibitors of the A. baumannii transporter MsbA, an LOS flippase. These molecules are potent and bactericidal against A. baumannii, including clinical carbapenem-resistant Acinetobacter baumannii isolates. Using cryo-electron microscopy and biochemical analysis, we show that the cerastecins adopt a serpentine configuration in the central vault of the MsbA dimer, stalling the enzyme and uncoupling ATP hydrolysis from substrate flipping. A derivative with optimized potency and pharmacokinetic properties showed efficacy in murine models of bloodstream or pulmonary A. baumannii infection. While resistance development is inevitable, targeting a clinically unexploited mechanism avoids existing antibiotic resistance mechanisms. Although clinical validation of LOS transport remains undetermined, the cerastecins may open a path to narrow-spectrum treatment modalities for important nosocomial infections. PubMed: 38649414DOI: 10.1038/s41564-024-01667-0 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.32 Å) |
Structure validation
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