Simulating the inhibition reaction of Mycobacterium tuberculosis L,D-transpeptidase 2 by carbapenems.
نویسندگان
چکیده
A theoretical free energy study describes the inactivation of a new tuberculosis target, the l,d-transpeptidase 2 enzyme. A new reaction mechanism of two carbapenem inhibitors is proposed and their molecular features are determined using QM/MM and PMF approaches. The theoretical findings with the new proposed mechanism agree in principle with the experimental data.
منابع مشابه
The peptidoglycan of stationary-phase Mycobacterium tuberculosis predominantly contains cross-links generated by L,D-transpeptidation.
Our understanding of the mechanisms used by Mycobacterium tuberculosis to persist in a "dormant" state is essential to the development of therapies effective in sterilizing tissues. Gene expression profiling in model systems has revealed a complex adaptive response thought to endow M. tuberculosis with the capacity to survive several months of combinatorial antibiotic treatment. We show here th...
متن کاملStructural basis for the inhibition of Mycobacterium tuberculosis l,d-transpeptidase by meropenem, a drug effective against extensively drug-resistant strains
Difficulty in the treatment of tuberculosis and growing drug resistance in Mycobacterium tuberculosis (Mtb) are a global health issue. Carbapenems inactivate L,D-transpeptidases; meropenem, when administered with clavulanate, showed in vivo activity against extensively drug-resistant Mtb strains. LdtMt2 (Rv2518c), one of two functional L,D-transpeptidases in Mtb, is predominantly expressed over...
متن کاملIn vitro cross-linking of Mycobacterium tuberculosis peptidoglycan by L,D-transpeptidases and inactivation of these enzymes by carbapenems.
The Mycobacterium tuberculosis peptidoglycan is cross-linked mainly by l,d-transpeptidases (LDTs), which are efficiently inactivated by a single β-lactam class, the carbapenems. Development of carbapenems for tuberculosis treatment has recently raised considerable interest since these drugs, in association with the β-lactamase inhibitor clavulanic acid, are uniformly active against extensively ...
متن کاملBuilding a Full-Atom Model of L,Dtranspeptidase 2 from Mycobacterium tuberculosis for Screening New Inhibitors
L,D-transpeptidase 2 from Mycobacterium tuberculosis plays a key role in the formation of the cell wall of a pathogen and catalyzes the cross-linking of growing peptidoglycan chains by non-classical 3-3 bonds, which causes resistance to a broad spectrum of penicillins. Molecular modeling of enzyme interactions with the N- and C-terminal tetrapeptide fragments of growing peptidoglycan chains has...
متن کاملToward antituberculosis drugs: in silico screening of synthetic compounds against Mycobacterium tuberculosisl,d-transpeptidase 2.
Mycobacterium tuberculosis (Mtb) the main causative agent of tuberculosis, is the main reason why this disease continues to be a global public health threat. It is therefore imperative to find a novel antitubercular drug target that is unique to the structural machinery or is essential to the growth and survival of the bacterium. One such target is the enzyme l,d-transpeptidase 2, also known as...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
- Chemical communications
دوره 51 63 شماره
صفحات -
تاریخ انتشار 2015