Structural and Functional Aspects of Class A Carbapenemases

نویسندگان

  • Thierry Naas
  • Laurent Dortet
  • Bogdan I. Iorga
چکیده

The fight against infectious diseases is probably one of the greatest public health challenges faced by our society, especially with the emergence of carbapenem-resistant gram-negatives that are in some cases pan-drug resistant. Currently,β-lactamase-mediated resistance does not spare even the newest and most powerful β-lactams (carbapenems), whose activity is challenged by carbapenemases. The worldwide dissemination of carbapenemases in gram-negative organisms threatens to take medicine back into the pre-antibiotic era since the mortality associated with infections caused by these "superbugs" is very high, due to limited treatment options. Clinically-relevant carbapenemases belong either to metallo-β- lactamases (MBLs) of Ambler class B or to serine-β-lactamases (SBLs) of Ambler class A and D enzymes. Class A carbapenemases may be chromosomally-encoded (SME, NmcA, SFC-1, BIC-1, PenA, FPH-1, SHV-38), plasmid-encoded (KPC, GES, FRI-1) or both (IMI). The plasmid-encoded enzymes are often associated with mobile elements responsible for their mobilization. These enzymes, even though weakly related in terms of sequence identities, share structural features and a common mechanism of action. They variably hydrolyse penicillins, cephalosporins, monobactams, carbapenems, and are inhibited by clavulanate and tazobactam. Three-dimensional structures of class A carbapenemases, in the apo form or in complex with substrates/inhibitors, together with site-directed mutagenesis studies, provide essential input for identifying the structural factors and subtle conformational changes that influence the hydrolytic profile and inhibition of these enzymes. Overall, these data represent the building blocks for understanding the structure-function relationships that define the phenotypes of class A carbapenemases and can guide the design of new molecules of therapeutic interest.

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

Structural Basis for Carbapenem-Hydrolyzing Mechanisms of Carbapenemases Conferring Antibiotic Resistance

Carbapenems (imipenem, meropenem, biapenem, ertapenem, and doripenem) are β-lactam antimicrobial agents. Because carbapenems have the broadest spectra among all β-lactams and are primarily used to treat infections by multi-resistant Gram-negative bacteria, the emergence and spread of carbapenemases became a major public health concern. Carbapenemases are the most versatile family of β-lactamase...

متن کامل

Comparing the Voice Handicap Index Scores in Groups with Structural and Functional Voice Disorders

Objective: The effects of voice disorders vary from person to person. Occupation, work environment, life, and family reaction are variables that affect one’s perception of his/her own as an impaired voice. Voice Handicap Index (VHI) has not yet been used to compare the degree of voice disorders. Assuming that the quality of life may be different under a variety of voice disorders and that diffe...

متن کامل

Urban neighborhood regeneration; Interpretive structural modeling of the factors affecting connected public spaces

Urban planning has emphasized quicker, lighter, and cheaper methods in recent years. According to urban studies, urban public spaces are valuable factors for urban neighborhood regeneration. Although, the concept of the network (connectivity in public spaces) is not new, and various authors and researchers had applied and adapted it to different areas of urban planning, it would be a new approa...

متن کامل

Structural-Functional Dynamism: An Alternative Approach to Spatial

Spatial planning approaches along with complication of societies are being changed. These changes and transformations have reflected themselves in increasing diversification of economic patterns, people, group, organization, and institution’s mobility. While in less developed network societies some of the concepts including “distance” and “movement “are relatively losing their importance , some...

متن کامل

Carbapenemases: the Versatile -Lactamases

INTRODUCTION .......................................................................................................................................................440 CLASSIFICATION SCHEMES ................................................................................................................................440 MOLECULAR CLASS A CARBAPENEMASES ............................................

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

عنوان ژورنال:

دوره 17  شماره 

صفحات  -

تاریخ انتشار 2016