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. 2003 Jun;47(6):1784-9.
doi: 10.1128/AAC.47.6.1784-1789.2003.

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

Daniel R Gentry  1 , Karen A Ingraham, Michael J Stanhope, Stephen Rittenhouse, Richard L Jarvest, Peter J O'Hanlon, James R Brown, David J Holmes
Affiliations

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

Daniel R Gentry et al. Antimicrob Agents Chemother. 2003 Jun.

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, and eukaryotic species, with streptococcal MetS being considerably less similar. We propose that the presence of metS2 in specific strains of S. pneumoniae is the result of horizontal gene transfer which has been driven by selection for resistance to some unknown class of naturally occurring antibiotics with similarities to recently reported synthetic MetS inhibitors.

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Figures

FIG. 1.
FIG. 1.
Distribution of resistance in 101 S. pneunomiae isolates to three synthetic small-molecule inhibitors of MetS. Resistance to MetS inhibitors SB-362916, SB-430537, and SB-441513 is measured as the MIC. The absolute numbers of isolates are shown above each bar.
FIG. 2.
FIG. 2.
Structures of SB-362916 and SB-441513. Me, methyl; Pr, propyl.
FIG. 3.
FIG. 3.
Scheme used to identify the resistance locus. EMS, ethyl methanesulfonate
FIG. 4.
FIG. 4.
Multiple-sequence alignment of MetS. The sequences shown are those of S. pneumoniae MetS1 (SpM1) and MetS2 (SpM2) and examples of closely related orthologs in public genome databases, B. anthracis MetS1 (BaM1) and MetS2 (BaM2), Thermoplasma acidophilum (Thac), a member of the domain Archaea, and Homo sapiens (Hosa). The locations of the conserved amino acid motifs HIGH and KMSKS, which are signatures for class I aminoacyl-tRNA, are indicated above the sequences. The dark, medium, and light shadings represent high (100%), medium (80%), and low (60%) levels of amino acid conservation, respectively. The figure was prepared with GeneDoc software (version 2.6002; K. B. Nicholas and H. B. Nicholas, Jr., 2000 [distributed by the authors at www.psu.edu/biomed/genedoc]).
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References

    1. Altschul, S. F., T. L. Madden, A. A. Schäffer, J. Zhang, Z. Zhang, W. Miller, and D. J. Lipman. 1997. Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res. 25:3389-3402. - PMC - PubMed
    1. Brown, J. R. 1998. Aminoacyl-tRNA synthetases. Evolution of a troubled family, p. 217-230. In J. Wiegel and M. W. W. Adams (ed.), Thermophiles: the keys to molecular evolution and the origin of life? Taylor and Francis Ltd., London, United Kingdom.
    1. Brown, J. R., J. Zhang, and J. E. Hodgson. 1998. A bacterial antibiotic resistance gene with eukaryotic origins. Curr. Biol. 8:R365-R367. - PubMed
    1. Dyke, K. G. H., S. P. Curnock, M. Golding, and W. C. Noble. 1991. Cloning of the gene conferring resistance to mupirocin in Staphylococcus aureus. FEMS Microbiol. Lett. 77:195-198. - PubMed
    1. Felmingham, D., and J. Washington. 1999. Trends in the antimicrobial susceptibility of bacterial respiratory tract pathogens—findings of the Alexander Project 1992-1996. J. Chemother. 11:5-21. - PubMed

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