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KatG-Mediated Oxidation Leading to Reduced Susceptibility of Bacteria to Kanamycin
Peter C Loewen1, P Malaka De Silva1, Lynda J Donald1
1Department of Microbiology, University of Manitoba, 45 Chancellor's Circle, Winnipeg, Manitoba R3T 2N2, Canada.
Abstract:
Resistance 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.
Insights
Mycobacterium tuberculosis KatG enzyme inactivates kanamycin, an aminoglycoside antibiotic. This KatG-mediated oxidation reduces antibiotic effectiveness, contributing to antibiotic resistance. Understanding this mechanism is crucial for developing new tuberculosis treatments.
Area of Science:
- Biochemistry
- Microbiology
- Drug Resistance
Background:
- Antibiotic resistance is a significant global health concern.
- In *Mycobacterium tuberculosis*, the enzyme KatG activates isoniazid but its role in aminoglycoside resistance was unknown.
Purpose of the Study:
- To investigate the interaction between aminoglycoside antibiotics and KatG.
- To determine if KatG influences susceptibility to aminoglycosides.
Main Methods:
- Enzyme kinetics assays to study KatG activity with kanamycin.
- Spectroscopic analysis to characterize the oxidation of kanamycin.
- Crystallization studies to identify potential binding sites.
Main Results:
- KatG was found to reduce susceptibility to kanamycin by oxidizing the antibiotic.
- Kanamycin acted as an electron donor for the KatG peroxidase reaction, becoming oxidized.
- The oxidized form of kanamycin exhibited reduced antibiotic activity.
- Crystallization data suggested a potential binding site for kanamycin on KatG.
Conclusions:
- The catalase-peroxidase KatG inactivates kanamycin, contributing to aminoglycoside resistance in *Mycobacterium tuberculosis*.
- This KatG-mediated inactivation mechanism represents a novel pathway in antibiotic resistance.
- Findings provide insights into drug-enzyme interactions and potential strategies to overcome resistance.
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