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 ~10⁴ 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 K_m and an increase in k_cat values. This study provides an insight into the molecular basis of interaction between meropenem and HSA.

Graphical abstract

Keywords:

• HSA–drug interaction
• carbapenem drugs
• fluorescence quenching
• three-dimensional fluorescence
• antibiotic resistance

Acknowledgements

Authors acknowledge Department of Biotechnology Award BT/HRD/NBA/34/01/2012 and Indian Council of Medical Research grant number 59/6/2009/BMS/TRM. MTR is thankful to University Grants Commission (New Delhi, India) for Dr. D S Kothari Postdoctoral Fellowship. SA acknowledges the Department of Biotechnology (New Delhi, India) for financial assistance in the form of studentship.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by the Department of Biotechnology, Ministry of Science and Technology [grant number BT/HRD/NBA/34/01/2012]; Indian Council of Medical Research [grant number 59/6/2009/BMS/TRM].