Variable sensitivity to bacterial methionyl-tRNA synthetase inhibitors reveals subpopulations of Streptococcus pneumoniae with two distinct methionyl-tRNA synthetase genes.

Antimicrobial Agents and Chemotherapy
Daniel R GentryDavid J Holmes

Abstract

As reported previously (J. R. Jarvest et al., J. Med. Chem. 45:1952-1962, 2002), potent inhibitors (at nanomolar concentrations) of Staphylococcus aureus methionyl-tRNA synthetase (MetS; encoded by metS1) have been derived from a high-throughput screening assay hit. Optimized compounds showed excellent activities against staphylococcal and enterococcal pathogens. We report on the bimodal susceptibilities of S. pneumoniae strains, a significant fraction of which was found to be resistant (MIC, > or =8 mg/liter) to these inhibitors. Using molecular genetic techniques, we have found that the mechanism of resistance is the presence of a second, distantly related MetS enzyme, MetS2, encoded by metS2. We present evidence that the metS2 gene is necessary and sufficient for resistance to MetS inhibitors. PCR analysis for the presence of metS2 among a large sample (n = 315) of S. pneumoniae isolates revealed that it is widespread geographically and chronologically, occurring at a frequency of about 46%. All isolates tested also contained the metS1 gene. Searches of public sequence databases revealed that S. pneumoniae MetS2 was most similar to MetS in Bacillus anthracis, followed by MetS in various non-gram-positive bacterial, archaeal,...Continue Reading

References

Jan 15, 1991·FEMS Microbiology Letters·K G DykeW C Noble
Apr 1, 1985·Antimicrobial Agents and Chemotherapy·R SutherlandA R White
Nov 21, 1995·Proceedings of the National Academy of Sciences of the United States of America·L S HåvarsteinD A Morrison
Sep 1, 1997·Nucleic Acids Research·S F AltschulD J Lipman
Jun 23, 1998·Current Biology : CB·J R BrownJ E Hodgson
Mar 8, 2000·Microbiology and Molecular Biology Reviews : MMBR·C R WoeseD Söll
Sep 7, 2001·Journal of Bacteriology·J HoskinsJ I Glass

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Citations

Apr 8, 2006·Nature Biotechnology·Molly B Schmid
Aug 22, 2007·Nature Chemical Biology·Peter A Smith, Floyd E Romesberg
Dec 13, 2006·Nature Reviews. Drug Discovery·David J PayneDavid L Pompliano
Mar 5, 2009·The Journal of Antimicrobial Chemotherapy·Ian A CritchleyUrs A Ochsner
May 30, 2009·Acta Crystallographica. Section F, Structural Biology and Crystallization Communications·Henrik IngvarssonTorsten Unge
Nov 19, 2008·Antimicrobial Agents and Chemotherapy·Louis S GreenThale C Jarvis
Jun 24, 2009·Antimicrobial Agents and Chemotherapy·James J Vecchione, Jason K Sello
Apr 2, 2008·Antimicrobial Agents and Chemotherapy·G C KedarRobert J Haselbeck
Feb 2, 2011·Antimicrobial Agents and Chemotherapy·Sayaka ShibataFrederick S Buckner
Sep 29, 2005·Antimicrobial Agents and Chemotherapy·Ian A CritchleyNebojsa Janjic
Sep 29, 2005·Antimicrobial Agents and Chemotherapy·Urs A OchsnerIan A Critchley
Nov 24, 2005·Antimicrobial Agents and Chemotherapy·Julian Gregston HurdleIan Chopra
Jun 15, 2012·BMC Evolutionary Biology·Cheryl P AndamJ Peter Gogarten
Aug 2, 2008·PloS One·Huaiqing ChenJing-Ren Zhang
Nov 16, 2010·Future Microbiology·Heike Brötz-Oesterhelt, Peter Sass
Nov 19, 2003·Proceedings of the National Academy of Sciences of the United States of America·Brian C JesterKevin M Devine
Apr 28, 2007·Expert Opinion on Investigational Drugs·Urs A OchsnerNebojsa Janjic
Jul 16, 2008·Current Opinion in Chemical Biology·Ian A Critchley, Urs A Ochsner
Nov 10, 2010·Annals of the New York Academy of Sciences·Michael N GwynnDavid J Payne
Aug 1, 2007·Expert Opinion on Drug Discovery·Tod P HollerLakshmi Narasimhan
Apr 28, 2011·FEMS Microbiology Reviews·Cheryl P AndamJohann Peter Gogarten
Jul 5, 2005·Drug Discovery Today·Christoph Freiberg, Heike Brötz-Oesterhelt
Aug 30, 2017·Antimicrobial Agents and Chemotherapy·Omeed FaghihFrederick S Buckner
Feb 13, 2019·Antimicrobial Agents and Chemotherapy·Frederick S BucknerErkang Fan
Jun 15, 2011·Nature Reviews. Microbiology·Cheryl P Andam, J Peter Gogarten
Jun 18, 2014·The Journal of Biological Chemistry·Ayome AbibiEd T Buurman
May 1, 2019·Proceedings of the National Academy of Sciences of the United States of America·Bradley E PoulsenDeborah T Hung
Apr 11, 2018·Acta Crystallographica. Section F, Structural Biology Communications·Ximena Barros-ÁlvarezWim G J Hol
Feb 14, 2021·International Journal of Molecular Sciences·Luping PangArthur Van Aerschot
Dec 14, 2006·ACS Chemical Biology·Sandro F Ataide, Michael Ibba
Apr 16, 2021·The Journal of Biological Chemistry·Gustavo Fernando MercaldiCelso Eduardo Benedetti
Mar 24, 2021·Antimicrobial Agents and Chemotherapy·Muhammad M HasanChristopher D Huston
Oct 8, 2021·Frontiers in Molecular Biosciences·Fernando Medeiros FilhoFabrício Alves Barbosa da Silva

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