3DWZ

Meropenem Covalent Adduct with TB Beta-lactamase

Summary for 3DWZ

• Entry DOI: 10.2210/pdb3dwz/pdb
• Related: 3cg5
• Descriptor: Beta-lactamase, PHOSPHATE ION, (2S,3R,4S)-4-{[(3S,5S)-5-(dimethylcarbamoyl)pyrrolidin-3-yl]sulfanyl}-2-[(2S,3R)-3-hydroxy-1-oxobutan-2-yl]-3-methyl-3,4-dihydro-2H-pyrrole-5-carboxylic acid, ... (4 entities in total)
• Functional Keywords: alpha-beta folded protein, protein-covalent adduct, antibiotic resistance, hydrolase, lipoprotein, membrane, palmitate, meropenem (open form), hydrolase-antibiotic complex, hydrolase/antibiotic
• Biological source: Mycobacterium tuberculosis
• Total number of polymer chains: 1
• Total formula weight: 28848.14

Authors

Tremblay, L.W.,Hugonnet, J.E.,Blanchard, J.S. (deposition date: 2008-07-23, release date: 2009-03-10, Last modification date: 2024-10-09)

Primary citation

Hugonnet, J.E.,Tremblay, L.W.,Boshoff, H.I.,Barry, C.E.,Blanchard, J.S.
Meropenem-clavulanate is effective against extensively drug-resistant Mycobacterium tuberculosis
Science, 323:1215-1218, 2009

PubMed Abstract: beta-lactam antibiotics are ineffective against Mycobacterium tuberculosis, being rapidly hydrolyzed by the chromosomally encoded blaC gene product. The carbapenem class of beta-lactams are very poor substrates for BlaC, allowing us to determine the three-dimensional structure of the covalent BlaC-meropenem covalent complex at 1.8 angstrom resolution. When meropenem was combined with the beta-lactamase inhibitor clavulanate, potent activity against laboratory strains of M. tuberculosis was observed [minimum inhibitory concentration (MIC(meropenem)) less than 1 microgram per milliliter], and sterilization of aerobically grown cultures was observed within 14 days. In addition, this combination exhibited inhibitory activity against anaerobically grown cultures that mimic the "persistent" state and inhibited the growth of 13 extensively drug-resistant strains of M. tuberculosis at the same levels seen for drug-susceptible strains. Meropenem and clavulanate are Food and Drug Administration-approved drugs and could potentially be used to treat patients with currently untreatable disease.

PubMed: 19251630
DOI: 10.1126/science.1167498

Experimental method

X-RAY DIFFRACTION (1.8 Å)