9NT0

OXA-23-meropenem, pH 7.5

Summary for 9NT0

• Entry DOI: 10.2210/pdb9nt0/pdb
• Descriptor: Beta-lactamase OXA-23, (4R,5S)-3-{[(3S,5S)-5-(dimethylcarbamoyl)pyrrolidin-3-yl]sulfanyl}-5-[(2S,3R)-3-hydroxy-1-oxobutan-2-yl]-4-methyl-4,5-d ihydro-1H-pyrrole-2-carboxylic acid, SULFATE ION, ... (4 entities in total)
• Functional Keywords: oxa, antibiotic resistance, inhibitor, meropenem, hydrolase
• Biological source: Acinetobacter baumannii
• Total number of polymer chains: 1
• Total formula weight: 31536.34

Authors

Smith, C.A.,Toth, M.,Stewart, N.K.,Vakulenko, S.B. (deposition date: 2025-03-17, release date: 2025-08-06, Last modification date: 2025-10-15)

Primary citation

Toth, M.,Stewart, N.K.,Quan, P.,Khan, M.M.K.,Cox, J.,Buynak, J.D.,Smith, C.A.,Vakulenko, S.B.
Dual mechanism of the OXA-23 carbapenemase inhibition by the carbapenem NA-1-157.
Antimicrob.Agents Chemother., 69:e0091825-e0091825, 2025

PubMed Abstract: Carbapenem-resistant continues to be a leading cause of life-threatening infections that result in high mortality rates. The major cause of carbapenem resistance in this pathogen is the production of class D carbapenemases, enzymes that inactivate the last resort carbapenem antibiotics, thus significantly diminishing the available therapeutic options. In this study, we evaluated the interaction of OXA-23, the most widely disseminated class D carbapenemase in clinical isolates, with the atypically modified carbapenem, NA-1-157. The MICs of this compound against strains producing OXA-23 were reduced from highly resistant levels observed for the commercial carbapenems meropenem and imipenem (16-128 µg/mL) to sensitive or intermediate levels (2-4 µg/mL). Kinetic studies showed that NA-1-157 inhibits the enzyme due to a significant decrease (>2,000-fold) in the deacylation rate relative to its closest structural analog, meropenem. Structural studies and molecular dynamics simulations demonstrated that inhibition is caused by both the inability of a water molecule to get close enough to the scissile bond to perform deacylation and by partial decarboxylation of the catalytic lysine residue upon formation of the acyl-enzyme intermediate.

PubMed: 40833279
DOI: 10.1128/aac.00918-25

Experimental method

X-RAY DIFFRACTION (1.6 Å)