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Antimicrob Agents Chemother. 2018 Jan 25;62(2). pii: e01510-17. doi: 10.1128/AAC.01510-17. Print 2018 Feb.

A Novel Mechanism of Inactivating Antibacterial Nitro Compounds in the Human Pathogen Staphylococcus aureus by Overexpression of a NADH-Dependent Flavin Nitroreductase.

Author information

1
University of Würzburg, Institute of Pharmacy and Food Chemistry, Würzburg, Germany.
2
University of Würzburg, Institute for Molecular Infection Biology, Würzburg, Germany.
3
National Centre for Radiation Research & Technology, Egyptian Atomic Energy Authority, Cairo, Egypt.
4
University of Geneva Hospitals, Genomic Research Laboratory, Service of Infectious Diseases, Geneva, Switzerland.
5
University of Würzburg, Institute for Molecular Infection Biology, Würzburg, Germany knut.ohlsen@uni-wuerzburg.de ulrike.holzgrabe@uni-wuerzburg.de.
6
University of Würzburg, Institute of Pharmacy and Food Chemistry, Würzburg, Germany knut.ohlsen@uni-wuerzburg.de ulrike.holzgrabe@uni-wuerzburg.de.

Abstract

Recently, the nitro-substituted bisquaternary bisnaphthalimides were reported to have substantial anti-infective activity against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). Here, we selected resistant S. aureus clones by cultivation in increasing concentrations of the most active compound, MT02. Interestingly, MT02-resistant variants induced a diffusible red color of the broth. Chromatographic and spectroscopic investigations revealed a stepwise reduction of the bisquaternary bisnaphthalimides' nitro groups to amino groups. The corresponding derivatives were completely inactive against staphylococci. RNA sequencing experiments revealed a strong overexpression of a novel oxidoreductase in MT02-resistant strains. Deletion mutants of this enzyme did not produce the red color and were not able to develop resistance against bisquaternary bisnaphthalimides. Biochemical reactions confirmed an NADH-dependent deactivation of the nitro-substituted compounds. Thus, this is the first report of a nitroreductase-based antibiotic resistance mechanism in the human pathogen S. aureus.

KEYWORDS:

Staphylococcus aureus; antibacterial nitro compounds; bacterial nitroreductases; bacterial resistance

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