Deoxynybomycins inhibit mutant DNA gyrase and rescue mice infected with fluoroquinolone-resistant bacteria

Elizabeth I. Parkinson; Joseph S. Bair; Bradley A. Nakamura; Hyang Y. Lee; Hani I. Kuttab; Emma H. Southgate; Stéphane Lezmi; Gee W. Lau; Paul J. Hergenrother

doi:10.1038/ncomms7947

Deoxynybomycins inhibit mutant DNA gyrase and rescue mice infected with fluoroquinolone-resistant bacteria

Elizabeth I. Parkinson, Joseph S. Bair, Bradley A. Nakamura, Hyang Y. Lee, Hani I. Kuttab, Emma H. Southgate, Stéphane Lezmi, Gee W. Lau, Paul J. Hergenrother

Research output: Contribution to journal › Article › peer-review

Abstract

Fluoroquinolones are one of the most commonly prescribed classes of antibiotics, but fluoroquinolone resistance (FQR) is widespread and increasing. Deoxynybomycin (DNM) is a natural-product antibiotic with an unusual mechanism of action, inhibiting the mutant DNA gyrase that confers FQR. Unfortunately, isolation of DNM is difficult and DNM is insoluble in aqueous solutions, making it a poor candidate for development. Here we describe a facile chemical route to produce DNM and its derivatives. These compounds possess excellent activity against FQR methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococci clinical isolates and inhibit mutant DNA gyrase in-vitro. Bacteria that develop resistance to DNM are re-sensitized to fluoroquinolones, suggesting that resistance that emerges to DNM would be treatable. Using a DNM derivative, the first in-vivo efficacy of the nybomycin class is demonstrated in a mouse infection model. Overall, the data presented suggest the promise of DNM derivatives for the treatment of FQR infections.

Original language	English (US)
Article number	6947
Journal	Nature communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms7947
State	Published - Apr 22 2015

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

Online availability

10.1038/ncomms7947

Library availability

Discover UIUC Full Text

Cite this

@article{57cd97db17084ebf8fe435a594dfb17a,

title = "Deoxynybomycins inhibit mutant DNA gyrase and rescue mice infected with fluoroquinolone-resistant bacteria",

abstract = "Fluoroquinolones are one of the most commonly prescribed classes of antibiotics, but fluoroquinolone resistance (FQR) is widespread and increasing. Deoxynybomycin (DNM) is a natural-product antibiotic with an unusual mechanism of action, inhibiting the mutant DNA gyrase that confers FQR. Unfortunately, isolation of DNM is difficult and DNM is insoluble in aqueous solutions, making it a poor candidate for development. Here we describe a facile chemical route to produce DNM and its derivatives. These compounds possess excellent activity against FQR methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococci clinical isolates and inhibit mutant DNA gyrase in-vitro. Bacteria that develop resistance to DNM are re-sensitized to fluoroquinolones, suggesting that resistance that emerges to DNM would be treatable. Using a DNM derivative, the first in-vivo efficacy of the nybomycin class is demonstrated in a mouse infection model. Overall, the data presented suggest the promise of DNM derivatives for the treatment of FQR infections.",

author = "Parkinson, {Elizabeth I.} and Bair, {Joseph S.} and Nakamura, {Bradley A.} and Lee, {Hyang Y.} and Kuttab, {Hani I.} and Southgate, {Emma H.} and St{\'e}phane Lezmi and Lau, {Gee W.} and Hergenrother, {Paul J.}",

note = "Funding Information: We thank Cubist Pharmaceuticals for generating the MRSA clinical isolate data (Fig. 2a) and providing DNA from those isolates. We thank Professor David C. Hooper for providing the plasmids pTRC-HisA-GyrA and pTRC-HisA-GyrB. We thank Professor Tim Fan, Professor Levent Dirikolu and Andrew Lee for technical assistance. This work was supported by the University of Illinois (P.J.H.) and the National Institutes of Health (NIH) Grant R01HL090699 (G.W.L.). E.I.P. is a National Science Foundation pre-doctoral fellow and an ACS Medicinal Chemistry pre-doctoral fellow. B.A.N. is a National Defense Science and Engineering pre-doctoral fellow. Publisher Copyright: {\textcopyright} 2015 Macmillan Publishers Limited. All rights reserved.",

year = "2015",

month = apr,

day = "22",

doi = "10.1038/ncomms7947",

language = "English (US)",

volume = "6",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Deoxynybomycins inhibit mutant DNA gyrase and rescue mice infected with fluoroquinolone-resistant bacteria

AU - Parkinson, Elizabeth I.

AU - Bair, Joseph S.

AU - Nakamura, Bradley A.

AU - Lee, Hyang Y.

AU - Kuttab, Hani I.

AU - Southgate, Emma H.

AU - Lezmi, Stéphane

AU - Lau, Gee W.

AU - Hergenrother, Paul J.

N1 - Funding Information: We thank Cubist Pharmaceuticals for generating the MRSA clinical isolate data (Fig. 2a) and providing DNA from those isolates. We thank Professor David C. Hooper for providing the plasmids pTRC-HisA-GyrA and pTRC-HisA-GyrB. We thank Professor Tim Fan, Professor Levent Dirikolu and Andrew Lee for technical assistance. This work was supported by the University of Illinois (P.J.H.) and the National Institutes of Health (NIH) Grant R01HL090699 (G.W.L.). E.I.P. is a National Science Foundation pre-doctoral fellow and an ACS Medicinal Chemistry pre-doctoral fellow. B.A.N. is a National Defense Science and Engineering pre-doctoral fellow. Publisher Copyright: © 2015 Macmillan Publishers Limited. All rights reserved.

PY - 2015/4/22

Y1 - 2015/4/22

N2 - Fluoroquinolones are one of the most commonly prescribed classes of antibiotics, but fluoroquinolone resistance (FQR) is widespread and increasing. Deoxynybomycin (DNM) is a natural-product antibiotic with an unusual mechanism of action, inhibiting the mutant DNA gyrase that confers FQR. Unfortunately, isolation of DNM is difficult and DNM is insoluble in aqueous solutions, making it a poor candidate for development. Here we describe a facile chemical route to produce DNM and its derivatives. These compounds possess excellent activity against FQR methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococci clinical isolates and inhibit mutant DNA gyrase in-vitro. Bacteria that develop resistance to DNM are re-sensitized to fluoroquinolones, suggesting that resistance that emerges to DNM would be treatable. Using a DNM derivative, the first in-vivo efficacy of the nybomycin class is demonstrated in a mouse infection model. Overall, the data presented suggest the promise of DNM derivatives for the treatment of FQR infections.

AB - Fluoroquinolones are one of the most commonly prescribed classes of antibiotics, but fluoroquinolone resistance (FQR) is widespread and increasing. Deoxynybomycin (DNM) is a natural-product antibiotic with an unusual mechanism of action, inhibiting the mutant DNA gyrase that confers FQR. Unfortunately, isolation of DNM is difficult and DNM is insoluble in aqueous solutions, making it a poor candidate for development. Here we describe a facile chemical route to produce DNM and its derivatives. These compounds possess excellent activity against FQR methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococci clinical isolates and inhibit mutant DNA gyrase in-vitro. Bacteria that develop resistance to DNM are re-sensitized to fluoroquinolones, suggesting that resistance that emerges to DNM would be treatable. Using a DNM derivative, the first in-vivo efficacy of the nybomycin class is demonstrated in a mouse infection model. Overall, the data presented suggest the promise of DNM derivatives for the treatment of FQR infections.

UR - http://www.scopus.com/inward/record.url?scp=84928922991&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84928922991&partnerID=8YFLogxK

U2 - 10.1038/ncomms7947

DO - 10.1038/ncomms7947

M3 - Article

C2 - 25907309

AN - SCOPUS:84928922991

SN - 2041-1723

VL - 6

JO - Nature Communications

JF - Nature Communications

M1 - 6947

ER -

Deoxynybomycins inhibit mutant DNA gyrase and rescue mice infected with fluoroquinolone-resistant bacteria

Abstract

ASJC Scopus subject areas

Online availability

Library availability

Related links

Fingerprint

Cite this