Molecular investigation of the structure-activity relationship of human Oligopeptide transporter 2 (PepT2) and polymyxin B

Abstract

Polymyxins are a class of antibiotics known for their potent activity against multidrug-resistant Gram-negative bacteria; however, their clinical usage is greatly limited to due to their renal toxicity. The recent research has revealed the interaction between polymyxin and human Oligopeptide transporter 2 (hPepT2). It was found that hPepT2 may be responsible for the renal reabsorption of polymyxins, which may greatly contribute to the toxic accumulation of polymyxins in the kidney. Therefore, understanding the interaction between polymyxins and hPepT2 enables us to strategically manipulate their interaction and then inhibit the toxic accumulation of polymyxins in the kidney. And to establish the structure-interaction relationship model of polymyxins and hPepTs forms the basis of designing new polymyxin-like antibiotics that has reduced nephrotoxicity. This study examined several residues of hPepT2 for their involvement in its recognition of polymyxins and hPepT2-mediated cellular uptake of polymyxins through functional mutagenesis.