ao8b00356_si_001.pdf (442.98 kB)
KatG-Mediated Oxidation Leading to Reduced Susceptibility of Bacteria to Kanamycin
journal contribution
posted on 2018-04-16, 08:13 authored by Peter
C. Loewen, P. Malaka De Silva, Lynda J. Donald, Jacek Switala, Jacylyn Villanueva, Ignacio Fita, Ayush KumarResistance
to antibiotics has become a serious problem for society,
and there are increasing efforts to understand the reasons for and
sources of resistance. Bacterial-encoded enzymes and transport systems,
both innate and acquired, are the most frequent culprits for the development
of resistance, although in Mycobacterium tuberculosis, the catalase-peroxidase, KatG, has been linked to the activation
of the antitubercular drug isoniazid. While investigating a possible
link between aminoglycoside antibiotics and the induction of oxidative
bursts, we observed that KatG reduces susceptibility to aminoglycosides.
Investigation revealed that kanamycin served as an electron donor
for the peroxidase reaction, reducing the oxidized ferryl intermediates
of KatG to the resting state. Loss of electrons from kanamycin was
accompanied by the addition of a single oxygen atom to the aminoglycoside.
The oxidized form of kanamycin proved to be less effective as an antibiotic.
Kanamycin inhibited the crystallization of KatG, but the smaller,
structurally related glycoside maltose did cocrystallize with KatG,
providing a suggestion as to the possible binding site of kanamycin.
History
Usage metrics
Categories
Keywords
Mycobacterium tuberculosisperoxidase reactiontransport systemsresistanceoxidative burstsantitubercular drug isoniazidglycoside maltoseaminoglycoside antibioticsBacterial-encoded enzymesKatG-Mediated Oxidationelectron donoroxygen atomReduced SusceptibilityKanamycin Resistanceferryl intermediatesbinding sitekanamycin
Licence
Exports
RefWorks
BibTeX
Ref. manager
Endnote
DataCite
NLM
DC