%0 Journal Article
%T Identification of Functional Regulatory Residues of the ¦Â-Lactam Inducible Penicillin Binding Protein in Methicillin-Resistant Staphylococcus aureus
%A Andreas N. Mbah
%A Raphael D. Isokpehi
%J Chemotherapy Research and Practice
%D 2013
%I Hindawi Publishing Corporation
%R 10.1155/2013/614670
%X Resistance to methicillin by Staphylococcus aureus is a persistent clinical problem worldwide. A mechanism for resistance has been proposed in which methicillin resistant Staphylococcus aureus (MRSA) isolates acquired a new protein called ¦Â-lactam inducible penicillin binding protein (PBP-2¡ä). The PBP-2¡ä functions by substituting other penicillin binding proteins which have been inhibited by ¦Â-lactam antibiotics. Presently, there is no structural and regulatory information on PBP-2¡ä protein. We conducted a complete structural and functional regulatory analysis of PBP-2¡ä protein. Our analysis revealed that the PBP-2¡ä is very stable with more hydrophilic amino acids expressing antigenic sites. PBP-2¡ä has three striking regulatory points constituted by first penicillin binding site at Ser25, second penicillin binding site at Ser405, and finally a single metallic ligand binding site at Glu657 which binds to ions. This report highlights structural features of PBP-2¡ä that can serve as targets for developing new chemotherapeutic agents and conducting site direct mutagenesis experiments. 1. Introduction Methicillin resistance (MR) by Staphylococcus aureus is a persistent clinical problem affecting many geographic locations worldwide [1¨C4]. Glycopeptides such as vancomycin and teicoplanin are often the choice in treating infections associated with methicillin-resistant S. aureus (MRSA), at times with little success [5]. The resistance of methicillin by Staphylococcus aureus has been documented to depend on several factors such as temperature [6], pH [7], NaCl concentration, and inoculum size [6, 8]. Even though methicillin-resistant staphylococci produce penicillinase, blocking of this enzyme do not affect the level of methicillin resistance [9]. The history of ever-increasing resistance among MRSA strains suggests that they are likely to be more prevalent in the future, thus severely restricting treatment options [10]. Penicillin-binding proteins (PBPs) are enzymes commonly expressed by MRSA during peptidoglycan synthesis, cell growth, and morphogenesis. The PBPs are inhibited by ¦Â-Lactam antibiotics such as methicillin and vancomycin by interrupting the biochemical functions at the D-Ala-D-Ala terminus of the peptidoglycan precursor [5, 11]. The expressions of PBPs in MRSA have been well documented in previous studies, with PBP-2 and PBP-3 proposed as the lethal targets for ¦Â-lactams action [12¨C14]. However, another mechanism for methicillin resistance have been reported in which MRSA isolates have acquired a new PBP protein called ¦Â-lactam inducible
%U http://www.hindawi.com/journals/cherp/2013/614670/