The basis for resistance to beta-lactam antibiotics by penicillin-binding protein 2a of methicillin-resistant Staphylococcus aureus

The Journal of Biological Chemistry
Cosimo FudaShahriar Mobashery

Abstract

Penicillin-binding protein 2a (PBP2a) of Staphylococcus aureus is refractory to inhibition by available beta-lactam antibiotics, resulting in resistance to these antibiotics. The strains of S. aureus that have acquired the mecA gene for PBP2a are designated as methicillin-resistant S. aureus (MRSA). The mecA gene was cloned and expressed in Escherichia coli, and PBP2a was purified to homogeneity. The kinetic parameters for interactions of several beta-lactam antibiotics (penicillins, cephalosporins, and a carbapenem) and PBP2a were evaluated. The enzyme manifests resistance to covalent modification by beta-lactam antibiotics at the active site serine residue in two ways. First, the microscopic rate constant for acylation (k2) is attenuated by 3 to 4 orders of magnitude over the corresponding determinations for penicillin-sensitive penicillin-binding proteins. Second, the enzyme shows elevated dissociation constants (Kd) for the non-covalent pre-acylation complexes with the antibiotics, the formation of which ultimately would lead to enzyme acylation. The two factors working in concert effectively prevent enzyme acylation by the antibiotics in vivo, giving rise to drug resistance. Given the opportunity to form the acyl enzyme sp...Continue Reading

References

Feb 1, 1986·Antimicrobial Agents and Chemotherapy·N H GeorgopapadakouY R Mauriz
Jan 1, 1997·Microbial Drug Resistance : MDR : Mechanisms, Epidemiology, and Disease·M G PinhoH De Lencastre
May 1, 1999·Antimicrobial Agents and Chemotherapy·G ZhaoL C Blaszczak
Feb 15, 2001·Proceedings of the National Academy of Sciences of the United States of America·W LeeS Mobashery
Aug 23, 2001·Proceedings of the National Academy of Sciences of the United States of America·M G PinhoA Tomasz
Nov 29, 2001·Proceedings of the National Academy of Sciences of the United States of America·D GolemiS Mobashery
May 29, 2002·Proceedings of the National Academy of Sciences of the United States of America·Mark C EnrightBrian G Spratt
Jun 14, 2003·The Journal of Antimicrobial Chemotherapy·S S RichterG V Doern
Sep 2, 2003·Journal of Bacteriology·Yuki KatayamaHenry F Chambers
Jan 27, 2004·Antimicrobial Agents and Chemotherapy·Yuki KatayamaHenry F Chambers

❮ Previous
Next ❯

Citations

May 20, 2011·European Journal of Clinical Microbiology & Infectious Diseases : Official Publication of the European Society of Clinical Microbiology·S D KotsakisE Petinaki
Oct 28, 2011·Biochemistry·Venkatesh V NemmaraR F Pratt
Mar 28, 2013·The Journal of Organic Chemistry·Roberta J Worthington, Christian Melander
Mar 2, 2012·The Journal of Antibiotics·Jihwan HwangMasayori Inouye
Dec 13, 2006·Nature Reviews. Drug Discovery·Lynn L Silver
Jan 31, 2009·Nature Reviews. Drug Discovery·Jia JiaYu Zong Chen
Jul 21, 2012·The Journal of Biological Chemistry·Andrew L LoveringNatalie C J Strynadka
Feb 16, 2005·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·Stan Deresinski
Dec 9, 2010·The Journal of Antimicrobial Chemotherapy·Donald BiekDirk A Thye
May 9, 2012·Antimicrobial Agents and Chemotherapy·Aneela Qamar, Dasantila Golemi-Kotra
Jun 20, 2012·Antimicrobial Agents and Chemotherapy·Alex G TherienLynn Miesel
Apr 18, 2007·Antimicrobial Agents and Chemotherapy·Dong-Hyeon Kwon, Chung-Dar Lu
Jan 1, 2013·Antimicrobial Agents and Chemotherapy·Ewan M HarrisonMark A Holmes
Apr 6, 2012·PloS One·Amrita LamaMichiko M Nakano
Dec 5, 2013·The Journal of Antimicrobial Chemotherapy·Ewan M HarrisonMark A Holmes
Oct 8, 2013·Applied and Environmental Microbiology·Ziye HuBoran Kartal
Jul 1, 2008·Expert Review of Clinical Pharmacology·Marion Skalweit Helfand
Jan 1, 2007·Expert Opinion on Drug Discovery·Malcolm Gp Page
Dec 14, 2007·Expert Opinion on Pharmacotherapy·David P Nicolau
Mar 30, 2013·Phytomedicine : International Journal of Phytotherapy and Phytopharmacology·Su-Hyun MunDong-Yeul Kwon
Jun 11, 2011·European Journal of Pharmacology·Zhong WangYong-Yan Wang
Nov 21, 2012·Annals of the New York Academy of Sciences·Timothy Palzkill
Jan 7, 2011·Journal of Clinical Pharmacology·Zhong WangYongyan Wang
Sep 15, 2015·Nature Chemical Biology·Patrick R GonzalesGautam Dantas
Jul 22, 2014·IUBMB Life·Jennifer FishovitzShahriar Mobashery

❮ Previous
Next ❯

Related Concepts

Related Feeds

Antifungals

An antifungal, also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis such as athlete's foot, ringworm, candidiasis, cryptococcal meningitis, and others. Discover the latest research on antifungals here.

Antimicrobial Resistance (ASM)

Antimicrobial resistance poses a significant threat to the continued successful use of antimicrobial agents for the treatment of bacterial infections.

Bacterial Cell Wall Structure (ASM)

Bacterial cell walls are made of peptidoglycan (also called murein), which is made from polysaccharide chains cross-linked by unusual peptides containing D-amino acids. Here is the latest research on bacterial cell wall structures.

Carbapenems

Carbapenems are members of the beta lactam class of antibiotics and are used for the treatment of severe or high-risk bacterial infections. Discover the latest research on carbapenems here.

Bacterial Cell Wall Structure

Bacterial cell walls are made of peptidoglycan (also called murein), which is made from polysaccharide chains cross-linked by unusual peptides containing D-amino acids. Here is the latest research on bacterial cell wall structures.

Antimicrobial Resistance

Antimicrobial resistance poses a significant threat to the continued successful use of antimicrobial agents for the treatment of bacterial infections.

Carbapenems (ASM)

Carbapenems are members of the beta lactam class of antibiotics and are used for the treatment of severe or high-risk bacterial infections. Discover the latest research on carbapenems here.

ASBMB Publications

The American Society for Biochemistry and Molecular Biology (ASBMB) includes the Journal of Biological Chemistry, Molecular & Cellular Proteomics, and the Journal of Lipid Research. Discover the latest research from ASBMB here.

Antifungals (ASM)

An antifungal, also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis such as athlete's foot, ringworm, candidiasis, cryptococcal meningitis, and others. Discover the latest research on antifungals here.