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Molecular basis of antibiotic multiresistance transfer in Staphylococcus aureus

Edwards, Jonathan S. and Betts, Laurie and Frazier, Monica L. and Pollet, Rebecca M. and Kwong, Stephen M. and Walton, William G. and Ballentine, W. Keith, III and Huang, Julianne J. and Habibi, Sohrab and Del Campo, Mark and Meier, Jordan L. and Dervan, Peter B. and Firth, Neville and Redinbo, Matthew R. (2013) Molecular basis of antibiotic multiresistance transfer in Staphylococcus aureus. Proceedings of the National Academy of Sciences of the United States of America, 110 (8). pp. 2804-2809. ISSN 0027-8424. PMCID PMC3581901. https://resolver.caltech.edu/CaltechAUTHORS:20130412-102745791

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Abstract

Multidrug-resistant Staphylococcus aureus infections pose a significant threat to human health. Antibiotic resistance is most commonly propagated by conjugative plasmids like pLW1043, the first vancomycin-resistant S. aureus vector identified in humans. We present the molecular basis for resistance transmission by the nicking enzyme in S. aureus (NES), which is essential for conjugative transfer. NES initiates and terminates the transfer of plasmids that variously confer resistance to a range of drugs, including vancomycin, gentamicin, and mupirocin. The NES N-terminal relaxase–DNA complex crystal structure reveals unique protein–DNA contacts essential in vitro and for conjugation in S. aureus. Using this structural information, we designed a DNA minor groove-targeted polyamide that inhibits NES with low micromolar efficacy. The crystal structure of the 341-residue C-terminal region outlines a unique architecture; in vitro and cell-based studies further establish that it is essential for conjugation and regulates the activity of the N-terminal relaxase. This conclusion is supported by a small-angle X-ray scattering structure of a full-length, 665-residue NES–DNA complex. Together, these data reveal the structural basis for antibiotic multiresistance acquisition by S. aureus and suggest novel strategies for therapeutic intervention.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1073/pnas.1219701110 DOIArticle
http://www.pnas.org/cgi/doi/10.1073/pnas.1219701110PublisherArticle
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3581901/PubMed CentralArticle
http://www.pnas.org/lookup/suppl/doi:10.1073/pnas.1219701110/-/DCSupplementalPublisherSupporting Information
ORCID:
AuthorORCID
Dervan, Peter B.0000-0001-8852-7306
Additional Information:© 2013 National Academy of Sciences. Edited by Christopher T. Walsh, Harvard Medical School, Boston, MA, and approved December 21, 2012 (received for review November 12, 2012). Published online before print January 28, 2013. This work was supported by National Institutes of Health Grants AI078924 (to M.R.R.) and GM51747 (to P.B.D.), by National Medical Research Council of Australia Grant 457454 (to S.M.K. and N.F.), by American Cancer Society Fellowship PF-10-015-01-CDD (to J.L.M.), and by the APS and GM/CA CAT. Author contributions: J.S.E., L.B., M.D.C., J.L.M., P.B.D., N.F., and M.R.R. designed research; J.S.E., L.B., M.L.F., R.M.P., S.M.K., W.G.W., W.K.B., J.J.H., S.H., M.D.C., J.L.M., and N.F. performed research; J.S.E., L.B., M.L.F., R.M.P., S.M.K., W.G.W., W.K.B., J.J.H., S.H., M.D.C., J.L.M., P.B.D., N.F., and M.R.R. analyzed data; and J.S.E., L.B., R.M.P., M.D.C., J.L.M., P.B.D., N.F., and M.R.R. wrote the paper. The authors declare no conflict of interest. This article is a PNAS Direct Submission. Database deposition: The atomic coordinates and structure factors have been deposited in the Protein Data Bank, www.pdb.org (PDB ID codes 4HT4 and 4HTE). This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1219701110/-/DCSupplemental.
Funders:
Funding AgencyGrant Number
NIHAI078924
NIHGM-51747
National Medical Research Council of Australia457454
American Cancer SocietyPF-10-015-01-CDD
GM/CA @ APSUNSPECIFIED
Subject Keywords:MRSA; USA300; F-plasmid; pSK41; hairpin
Issue or Number:8
PubMed Central ID:PMC3581901
Record Number:CaltechAUTHORS:20130412-102745791
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20130412-102745791
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:37911
Collection:CaltechAUTHORS
Deposited By: Jason Perez
Deposited On:12 Apr 2013 18:14
Last Modified:26 Nov 2019 11:15

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