X
XLinkedinWhatsAppTelegramTelegram
0
Read this article in:

How allosteric control of Staphylococcus aureus penicillin binding protein 2a enables methicillin resistance and physiological function

The ability of an anti-MRSA β-lactam antibiotic to stimulate allosteric opening of the active site opens an unprecedented realm for β-lactam antibiotic structure-based design.

11 October 2013
X
XLinkedinWhatsAppTelegramTelegram
0

The expression of penicillin binding protein 2a (PBP2a) is the basis for the broad clinical resistance to the β-lactam antibiotics by methicillin-resistant Staphylococcus aureus (MRSA). The high-molecular mass penicillin binding proteins of bacteria catalyze in separate domains the transglycosylase and transpeptidase activities required for the biosynthesis of the peptidoglycan polymer that comprises the bacterial cell wall. In bacteria susceptible to β-lactam antibiotics, the transpeptidase activity of their penicillin binding proteins (PBPs) is lost as a result of irreversible acylation of an active site serine by the β-lactam antibiotics. In contrast, the PBP2a of MRSA is resistant to β-lactam acylation and successfully catalyzes the DD-transpeptidation reaction necessary to complete the cell wall.

The inability to contain MRSA infection with β-lactam antibiotics is a continuing public health concern. We report herein the identification of an allosteric binding domain-a remarkable 60 Å distant from the DD-transpeptidase active site-discovered by crystallographic analysis of a soluble construct of PBP2a. When this allosteric site is occupied, a multiresidue conformational change culminates in the opening of the active site to permit substrate entry. This same crystallographic analysis also reveals the identity of three allosteric ligands: muramic acid (a saccharide component of the peptidoglycan), the cell wall peptidoglycan, and ceftaroline, a recently approved anti-MRSA β-lactam antibiotic. The ability of an anti-MRSA β-lactam antibiotic to stimulate allosteric opening of the active site, thus predisposing PBP2a to inactivation by a second β-lactam molecule, opens an unprecedented realm for β-lactam antibiotic structure-based design.

Otero LH, Rojas-Altuve A, Llarrull LI, Carrasco-López C, Kumarasiri M, Lastochkin E, Fishovitz J, Dawley M, Hesek D, Lee M, Johnson JW, Fisher JF, Chang M, Mobashery S, Hermoso JA. How allosteric control of Staphylococcus aureus penicillin binding protein 2a enables methicillin resistance and physiological function. Proc Natl Acad Sci U S A. 2013 Oct 1. [Epub ahead of print]

Article Comments

This area is not intended to be a place to consult authors about their articles, but rather a place for open discussion among pig333.com users.
Leave a new Comment

Access restricted to 333 users. In order to post a comment you must be logged in.

You are not subscribed to this list pig333.com in 3 minutes

Weekly newsletter with all the pig333.com updates

Log in and sign up on the list

Related articles

MRSA thrives even without antibiotics

17-Oct-2011
The MRSA bacterium, which is resistant to antibiotics, has spread rapidly in the past few years on pig farms. Extensive use of antibiotics is thought to help it spread, but reducing the use of antibiotics is not enough to eliminate MRSA on pig farms.
You are not subscribed to this list Swine News

Swine industry news in your email

Log in and sign up on the list