Defining the architecture of KPC-2 Carbapenemase: identifying allosteric networks to fight antibiotics resistance

Scientific Reports
Ioannis GaldadasShozeb Haider

Abstract

The rise of multi-drug resistance in bacterial pathogens is one of the grand challenges facing medical science. A major concern is the speed of development of β-lactamase-mediated resistance in Gram-negative species, thus putting at risk the efficacy of the most recently approved antibiotics and inhibitors, including carbapenems and avibactam, respectively. New strategies to overcome resistance are urgently required, which will ultimately be facilitated by a deeper understanding of the mechanisms that regulate the function of β-lactamases such as the Klebsiella Pneumoniae carbapenemases (KPCs). Using enhanced sampling computational methods together with site-directed mutagenesis, we report the identification of two "hydrophobic networks" in the KPC-2 enzyme, the integrity of which has been found to be essential for protein stability and corresponding resistance. Present throughout the structure, these networks are responsible for the structural integrity and allosteric signaling. Disruption of the networks leads to a loss of the KPC-2 mediated resistance phenotype, resulting in restored susceptibility to different classes of β-lactam antibiotics including carbapenems and cephalosporins. The "hydrophobic networks" were found to ...Continue Reading

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Citations

Jun 5, 2019·Experimental Biology and Medicine·Ben A Shurina, Richard C Page
Aug 1, 2019·The Journal of Antimicrobial Chemotherapy·Stephan GöttigThomas A Wichelhaus
Jun 30, 2019·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Haoqi WangSandun Fernando
Nov 26, 2020·Antibiotics·Eleonora GianquintoFrancesca Spyrakis
Dec 10, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Alessandro PiraMatteo Ceccarelli
Nov 3, 2020·Frontiers in Microbiology·Eun-Jeong YoonSeok Hoon Jeong
Sep 28, 2021·The Journal of Antimicrobial Chemotherapy·Shazad MushtaqDavid M Livermore
Oct 9, 2021·Frontiers in Microbiology·Edgar OlehnovicsShozeb Haider

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Methods Mentioned

BETA
X-ray
NMR
acylation
electrophoresis

Software Mentioned

VMD
HTMD
MolPX
SHAKE
GAFF2
HMMER
Desmond
ACEMD
Pro
Skylign

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