title: Interaction of meropenem with 'N' and 'B' isoforms of human serum albumin: a spectroscopic and molecular docking study.
abstract: Carbapenems are used to control the outbreak of β-lactamases expressing bacteria. The effectiveness of drugs is influenced by its interaction with human serum albumin (HSA). Strong binding of carbapenems to HSA may lead to decreased bioavailability of the drug. The non-optimal drug dosage will provide a positive selection pressure on bacteria to develop resistance. Here, we investigated the interaction between meropenem and HSA at physiological pH 7.5 (N-isoform HSA) and non-physiological pH 9.2 (B-isoform HSA). Results showed that meropenem quenches the fluorescence of both 'N' and 'B' isoforms of HSA (ΔG < 0 and binding constant ~10(4) M(-1)). Electrostatic interactions and van der Waal interactions along with H-bonds stabilized the complex of meropenem with 'N' and 'B' isoforms of HSA, respectively. Molecular docking results revealed that meropenem binds to HSA near Sudlow's site II (subdomain IIIA) close to Trp-214 with a contribution of a few residues of subdomain IIA. CD spectroscopy showed a change in the conformation of both the isoforms of HSA upon meropenem binding. The catalytic efficiency of HSA (only N-isoform) on p-nitrophenyl acetate was increased primarily due to a decrease in Km and an increase in kcat values. This study provides an insight into the molecular basis of interaction between meropenem and HSA.
authors.affiliation: a Medical Microbiology and Molecular Biology Laboratory, Interdisciplinary Biotechnology Unit , Aligarh Muslim University , Aligarh , UP 202 002 , India.
authors.forename: Md Tabish
authors.initials: MT
authors.lastname: Rehman
authors.affiliation: a Medical Microbiology and Molecular Biology Laboratory, Interdisciplinary Biotechnology Unit , Aligarh Muslim University , Aligarh , UP 202 002 , India.
authors.forename: Sarfraz
authors.initials: S
authors.lastname: Ahmed
authors.affiliation: a Medical Microbiology and Molecular Biology Laboratory, Interdisciplinary Biotechnology Unit , Aligarh Muslim University , Aligarh , UP 202 002 , India.
authors.forename: Asad U
authors.initials: AU
authors.lastname: Khan
mesh_terms: D001665:Binding Sites; D002942:Circular Dichroism; D004789:Enzyme Activation; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D007700:Kinetics; D000077731:Meropenem; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D011485:Protein Binding; D011487:Protein Conformation; D020033:Protein Isoforms; D012709:Serum Albumin / Q000737:chemistry* / Q000378:metabolism; D013050:Spectrometry, Fluorescence; D013057:Spectrum Analysis / Q000379:methods; D013816:Thermodynamics; D013845:Thienamycins / Q000737:chemistry* / Q000378:metabolism
chemical_list: D020033:Protein Isoforms; D012709:Serum Albumin; D013845:Thienamycins; D000077731:Meropenem
keywords: HSA–drug interaction; antibiotic resistance; carbapenem drugs; fluorescence quenching; three-dimensional fluorescence