posted on 2015-12-17, 00:32authored byJacqueline
C. Hargis, Sai Lakshmana Vankayala, Justin K. White, H. Lee Woodcock
Bacterial
resistance to standard (i.e., β-lactam-based) antibiotics
has become a global pandemic. Simultaneously, research into the underlying
causes of resistance has slowed substantially, although its importance
is universally recognized. Key to unraveling critical details is characterization
of the noncovalent interactions that govern binding and specificity
(DD-peptidases, antibiotic targets, versus β-lactamases, the
evolutionarily
derived enzymes that play a major role in resistance) and ultimately
resistance as a whole. Herein, we describe a detailed investigation
that elicits new chemical insights into these underlying intermolecular
interactions. Benzylpenicillin and a novel β-lactam peptidomimetic
complexed to the Stremptomyces R61
peptidase are examined using an arsenal of computational techniques:
MD simulations, QM/MM calculations, charge perturbation analysis,
QM/MM orbital analysis, bioinformatics, flexible receptor/flexible
ligand docking, and computational ADME predictions. Several key molecular
level interactions are identified that not only shed light onto fundamental
resistance mechanisms, but also offer explanations for observed specificity.
Specifically, an extended π–π network is elucidated
that suggests antibacterial resistance has evolved, in part, due to
stabilizing aromatic interactions. Additionally, interactions between
the protein and peptidomimetic substrate are identified and characterized.
Of particular interest is a water-mediated salt bridge between Asp217
and the positively charged N-terminus of the peptidomimetic, revealing
an interaction that may significantly contribute to β-lactam
specificity. Finally, interaction information is used to suggest modifications
to current β-lactam compounds that should both improve binding
and specificity in DD-peptidases and their physiochemical properties.