The Plasma Protein Binding Proteome of Ertapenem: A Novel Compound-Centric Proteomic Approach for Elucidating Drug-Plasma Protein Binding Interactions.
Ertapenem is an important first-line carbapenem antibiotic used for the treatment of aerobic Gram-negative bacterial infections. It is the only marketed carbapenem that is highly bound to plasma proteins and displays a concentration-dependent and saturable plasma protein binding profile. To date, the plasma components responsible for sequestering ertapenems antibacterial activity remain uncharacterized. In the present study, we have employed an orthogonal, multiplatform approach, including novel compound-centric displacement proteomics and surface plasmon resonance to characterize the plasma protein binding proteome of ertapenem. In proof-of-concept, the capacity of physiological cocktails of the identified plasma proteins to inhibit the antibacterial activity of ertapenem was assessed with in vitro microbiological assays. We show that fibrinogen, complement C4, haptoglobulin, α-1-antitrypsin, fibronectin, transferrin, immunoglobulin G, hemopexin, and humans serum albumin are responsible for the majority of the sequestering activity in plasma. No binding was observed to α-1-acid-glycoprotein. The findings of this study have broad reaching implications for antibiotic drug design and for dose tailoring to suit the plasma protein levels of individual patients in order to maximize the clinical efficacy of important first-line antibiotics such as ertapenem.
Priority Research Centre in Reproductive Science, School of Environmental and Life Sciences, University of Newcastle , Callaghan, New South Wales 2308, Australia.
Mark A
MA
Baker
Facility for Drug Development and Innovation, Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University , 381 Royal Parade, Parkville, Victoria 3052, Australia.
Elena K
EK
Schneider
Institute for Molecular Bioscience, The University of Queensland , 306 Carmody Road, St Lucia, Queensland 4072, Australia.
Johnny
J
X Huang
Institute for Molecular Bioscience, The University of Queensland , 306 Carmody Road, St Lucia, Queensland 4072, Australia.
Matthew A
MA
Cooper
Facility for Drug Development and Innovation, Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University , 381 Royal Parade, Parkville, Victoria 3052, Australia.|Monash Biomedicine Discovery Institute, Department of Microbiology, Monash University , Clayton, Victoria 3800, Australia.
Jian
J
Li
Facility for Drug Development and Innovation, Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University , 381 Royal Parade, Parkville, Victoria 3052, Australia.
Tony
T
Velkov
D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D001798:Blood Proteins / Q000378:metabolism*; D000077727:Ertapenem; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D020543:Proteome / Q000378:metabolism; D040901:Proteomics / Q000295:instrumentation / Q000379:methods*; D013203:Staphylococcal Infections / Q000188:drug therapy; D013211:Staphylococcus aureus / Q000187:drug effects; D047090:beta-Lactams / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D001798:Blood Proteins; D020543:Proteome; D047090:beta-Lactams; D000077727:Ertapenem