9D7B

OXA-58-NA-1-157 7.5 min complex

Summary for 9D7B

• Entry DOI: 10.2210/pdb9d7b/pdb
• Related: 9D78 9D79 9D7A
• Descriptor: Beta-lactamase, (5R)-3-{[(3S,5S)-5-(dimethylcarbamoyl)pyrrolidin-3-yl]sulfanyl}-5-[(2S,3R)-3-hydroxy-1-oxobutan-2-yl]-5-methyl-4,5-dihydro-1H-pyrrole-2-carboxylic acid, ACETATE ION, ... (4 entities in total)
• Functional Keywords: beta-lactamase, carbapenemase, antibiotic resistance, inhibitor, hydrolase, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Acinetobacter baumannii
• Total number of polymer chains: 4
• Total formula weight: 127485.78

Authors

Smith, C.A.,Maggiolo, A.O.,Toth, M.,Vakulenko, S.B. (deposition date: 2024-08-16, release date: 2024-12-11, Last modification date: 2024-12-25)

Primary citation

Toth, M.,Stewart, N.K.,Maggiolo, A.O.,Quan, P.,Khan, M.M.K.,Buynak, J.D.,Smith, C.A.,Vakulenko, S.B.
Decarboxylation of the Catalytic Lysine Residue by the C5 alpha-Methyl-Substituted Carbapenem NA-1-157 Leads to Potent Inhibition of the OXA-58 Carbapenemase.
Acs Infect Dis., 10:4347-4359, 2024

PubMed Abstract: Antibiotic resistance in bacteria is a major global health concern. The wide spread of carbapenemases, bacterial enzymes that degrade the last-resort carbapenem antibiotics, is responsible for multidrug resistance in bacterial pathogens and has further significantly exacerbated this problem. is one of the leading nosocomial pathogens due to the acquisition and wide dissemination of carbapenem-hydrolyzing class D β-lactamases, which have dramatically diminished available therapeutic options. Thus, new antibiotics that are active against multidrug-resistant and carbapenemase inhibitors are urgently needed. Here we report characterization of the interaction of the C5α-methyl-substituted carbapenem NA-1-157 with one of the clinically important class D carbapenemases, OXA-58. Antibiotic susceptibility testing shows that the compound is more potent than commercial carbapenems against OXA-58-producing, with a clinically sensitive MIC value of 1 μg/mL. Kinetic studies demonstrate that NA-1-157 is a very poor substrate of the enzyme due mainly to a significantly reduced deacylation rate. Mass spectrometry analysis shows that inhibition of OXA-58 by NA-1-157 proceeds through both the classical acyl-enzyme intermediate and a reversible covalent species. Time-resolved X-ray crystallographic studies reveal that upon acylation of the enzyme, the compound causes progressive decarboxylation of the catalytic lysine residue, thus severely impairing deacylation. Overall, this study demonstrates that the carbapenem NA-1-157 is highly resistant to degradation by the OXA-58 carbapenemase.

PubMed: 39601221
DOI: 10.1021/acsinfecdis.4c00671

Experimental method

X-RAY DIFFRACTION (1.99 Å)