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Bacteria Subsisting on Antibiotics

Bacteria Subsisting on Antibiotics. Gautam Dantas Church Lab CEGS Annual Grantee Meeting - 2008. in US: MRSA kills more people than AIDS. US reported MRSA infections [1000’s]. 2006: 18,964. 2006: 14,627. Agency for healthcare research and quality, 2006.

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Bacteria Subsisting on Antibiotics

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  1. Bacteria Subsisting on Antibiotics Gautam Dantas Church Lab CEGS Annual Grantee Meeting - 2008

  2. in US: MRSA kills more people than AIDS US reported MRSA infections [1000’s] 2006: 18,964 2006: 14,627 Agency for healthcare research and quality, 2006

  3. Mechanisms of antibiotic resistance antibiotic modification efflux target modification

  4. Proc. Nat. Acad. Sci.70:2276 (1973) resistance gene origin hypothesis: antibiotic resistance genes originated as producer self immunity and was transferred to human pathogens

  5. Science 312:374 (2006)

  6. many antibiotics are produced in the environment, but it is likely that they undergo further biological transformations

  7. Bacteria subsisting on antibiotics are widely distributed in the environment NO GROWTH GROWTH G. Dantas., M. Sommer et al. Science 320:100 (2008)

  8. Antibiotic eaters are phylogenetically diverse G. Dantas., M. Sommer et al. Science 320:100 (2008)

  9. microbes subsisting on antibiotics are phylogenetically diverse they comprise of 3 out the 4 major phyla of human microbiomes compared to antibiotic producer organisms they constitute a more accessible reservoir of resistance 27% of the phylogenetic nearest named isolates are pathogens

  10. Bacteria subsisting on antibiotics are extremely resistant G. Dantas., M. Sommer et al. Science 320:100 (2008)

  11. G. Dantas., M. Sommer et al. Science 320:100 (2008)

  12. using functional genomic selections we have identified more than 150 unique antibiotic resistance genes from antibiotic eaters

  13. Experiments by: G. Dantas, M. Sommer. Unpublished data Gentamicin resistance from eater vs. Salmonella enterica subsp. enterica serovar Typhimurium genomic island I

  14. resistance genes from some antibiotic catabolizers are identical to resistance genes of pathogens at the nucleotide level

  15. best genetic support for producer hypothesis: >gi|27461214|gb|AY082011.1| Enterococcusfaecium strain 10/96A vanD gene cluster, complete sequence; and ISEfa4 insertion sequence element>gi|4104707:67-693 Streptomyces toyocaensis D-ala-D-ala dipeptidase (vanXst) gene, complete cds; and unknown gene ANTIMICROBIAL AGENTS AND CHEMOTHERAPY 42: 2215 (1998), Science 312:374 (2006), Nature Reviews Microbiology 5:175 (2007)

  16. Producer vs. Pathogen

  17. best homology between resistance gene from producer and pathogen: 66% identity @ nucleotide level homology between resistance gene from eater and pathogen: 98.5%, 99.9%, 99.9%, 100% identity @ nucleotide level

  18. some antibiotic resistance genes acquired by pathogens by HGT may have originated from antibiotic eaters

  19. Acknowledgements Morten Sommer George Church John Aach Duhee Bang Jay Lee Church Lab Rantimi Oluwasegun (Cornell) Jay Shendure (U.W.) Lynn Bry (BWH Pathology) Roberto Kolter (HMS) Peter Girguis, Hellen White (Harvard) Will Haas (HMS) Wayne Curtis (Penn State) David Ellison

  20. publications about antibiotic resistance

  21. Experimental Design resuspend in minimal media toothpick passage 1 4xfilter 500uL Innoculum 11 soils X 18 antibiotics toothpick passage 2 plate on solid (100,1,0.01uL, no carbon) liquid passage of clones restreak Experiments by: G. Dantas, M. Sommer, R. Oluwasegun.

  22. 11 soils: pristine, farm, urban 18 antibiotics: chemical class: beta-lactams quinolones sulfonamides amphenicols aminoglycosides glycopeptides amino-acid deriv origin: natural products semi-synthetic synthetic compounds

  23. Penicillin Catabolism in Action G. Dantas., M. Sommer et al. Science 320:100 (2008)

  24. Penicillin Catabolism in Action G. Dantas., M. Sommer et al. Science 320:100 (2008)

  25. some antibiotic resistance genes acquired by pathogens by HGT may have originated from antibiotic eaters

  26. Experiments by: G. Dantas, M. Sommer. Unpublished data >gi|94960156|gb|DQ519091.1| Acinetobacter baumannii strain DB60079/01 class I integron

  27. gi|83627312|dbj|AB207867.1|_Es TCCGGTGCGGGGACGGCTGCTCAGTGTTGCGCCTGTGTTCGCACGTTCGTGE_AB95Da04_01_mgRes1_R.trim.f ---------------------------------TCTGTTCGCACGTTCGT * ***************gi|83627312|dbj|AB207867.1|_Es ATCGGTGCGTTCTGATCTTCGCGTCAGACATTGCCGCGGCGCGGGCACAAGE_AB95Da04_01_mgRes1_R.trim.f ATCGGTGCGTTCTGATCTTCGCGTCAGACATTGCCGCGGCGCGGGCACAA **************************************************gi|83627312|dbj|AB207867.1|_Es CAAAAAGCCCGGCATCGCTGCCGGGCTCCGGCCCCGTCCTTGGGGCCTTGGE_AB95Da04_01_mgRes1_R.trim.f CAAAAAGCCCGGCATCGCTGCCGGGCTCCGGCCCCGTCCTTGGGGCCTTG **************************************************gi|83627312|dbj|AB207867.1|_Es ATGTCGGGTCGTTGCCGGGATCGGACCGCGCTGGCGCGGTCCGGTTCCCTGE_AB95Da04_01_mgRes1_R.trim.f ATGTCGGGTCGTTGCCGGGATCGGACCGCGCTGGCGCGGTCCGGTTCCCT **************************************************gi|83627312|dbj|AB207867.1|_Es GACGACCGGGCCAACCGGATCAGAAATCCATGCCGCCCATGCCGCCCATAGE_AB95Da04_01_mgRes1_R.trim.f GACGACCGGGCCAACCGGATCAGAAATCCATGCCGCCCATGCCGCCCATA **************************************************gi|83627312|dbj|AB207867.1|_Es CCGCCAGCACCCGGCATGGCCGGCTCTTCCTTCTTCGGCACTTCGGCCACGE_AB95Da04_01_mgRes1_R.trim.f CCGCCAGCACCCGGCATGGCCGGCTCTTCCTTCTTCGGCACTTCGGCCAC **************************************************gi|83627312|dbj|AB207867.1|_Es GACCACTTCGGTCGTGATCGCAAGGCCGGCGACGGAAGCGGCGTGCTGCAGE_AB95Da04_01_mgRes1_R.trim.f GACCACTTCGGTCGTGATCGCAAGGCCGGCGACGGAAGCGGCGTGCTGCA **************************************************gi|83627312|dbj|AB207867.1|_Es GGGCCGAGCGGGTCACCTTGGTCGGGTCCAGGATGCCCATGGCGATCATGGE_AB95Da04_01_mgRes1_R.trim.f GGGCCGAGCGGGTCACCTTGGTCGGGTCCAGGATGCCCATGGCGATCATG **************************************************gi|83627312|dbj|AB207867.1|_Es TCGCCGAACTCGCCGGTGGCGGCGTTGTAGCCGTAGCTGCCTTCGCCGGCGE_AB95Da04_01_mgRes1_R.trim.f TCGCCGAACTCGCCGGTGGCGGCGTTGTAGCCGTAGCTGCCTTCGCCGGC **************************************************gi|83627312|dbj|AB207867.1|_Es CTTGACGTTGGCCACGATCACGCTCGGTTCTTCACCGGCGTTGGCCACGAGE_AB95Da04_01_mgRes1_R.trim.f CTTGACGTTGGCCACGATCACGCTCGGTTCTTCACCGGCGTTGGCCACGA **************************************************gi|83627312|dbj|AB207867.1|_Es TGGCGCGCAGCGGGGCTTCCAGCGCACGGCGGGTGATGGCGATGCCCAGGGE_AB95Da04_01_mgRes1_R.trim.f TGGCGCGCAGCGGGGCTTCCAGCGCACGGCGGGTGATGGCGATGCCCAGG **************************************************gi|83627312|dbj|AB207867.1|_Es TTCTGGTCTTCGTTGATGCCCTGCCAGGGCAGATCCGTGCACAGCACCTTGE_AB95Da04_01_mgRes1_R.trim.f TTCTGGTCTTCGTTGATGCCCTGCCAGGGCAGATCCGTGCACAGCACCTT **************************************************gi|83627312|dbj|AB207867.1|_Es GCCGTAGAAGAACAGCAAGGCCGCCAATGCCTGACGATGCGTGGAGACCGGE_AB95Da04_01_mgRes1_R.trim.f GCCGTAGAAGAACAGCAAGGCCGCCAATGCCTGACGATGCGTGGAGACCG **************************************************gi|83627312|dbj|AB207867.1|_Es AAACCTTGCGCTCGTTCGCCAGCCAGGACAGAAATGCCTCGACTTCGCTGGE_AB95Da04_01_mgRes1_R.trim.f AAACCTTGCGCTCGTTCGCCAGCCAGGACAGAAATGCCTCGACTTCGCTG **************************************************gi|83627312|dbj|AB207867.1|_Es CTGCCCAAGGTTGCCGGGTGACGCACACCGTGGAAACGGATGAAGGCACGGE_AB95Da04_01_mgRes1_R.trim.f CTGCCCAAGGTTGCCGGGTGACGCACACCGTGGAAACGGATGAAGGCACG **************************************************gi|83627312|dbj|AB207867.1|_Es AACCCAGTGGACATAAGCCTGTTCGGTTGGTAAGCTGTAATGCAAGTAGCGE_AB95Da04_01_mgRes1_R.trim.f AACCCAGTGGACATAAGCCT------------------------------ ******************** gi|83627312|dbj|AB207867.1|_Es TCCGGTGCGGGGACGGCTGCTCAGTGTTGCGCCTGTGTTCGCACGTTCGTGE_AB95Da04_01_mgRes1_R.trim.f ---------------------------------TCTGTTCGCACGTTCGT * ***************gi|83627312|dbj|AB207867.1|_Es ATCGGTGCGTTCTGATCTTCGCGTCAGACATTGCCGCGGCGCGGGCACAAGE_AB95Da04_01_mgRes1_R.trim.f ATCGGTGCGTTCTGATCTTCGCGTCAGACATTGCCGCGGCGCGGGCACAA **************************************************gi|83627312|dbj|AB207867.1|_Es CAAAAAGCCCGGCATCGCTGCCGGGCTCCGGCCCCGTCCTTGGGGCCTTGGE_AB95Da04_01_mgRes1_R.trim.f CAAAAAGCCCGGCATCGCTGCCGGGCTCCGGCCCCGTCCTTGGGGCCTTG **************************************************gi|83627312|dbj|AB207867.1|_Es ATGTCGGGTCGTTGCCGGGATCGGACCGCGCTGGCGCGGTCCGGTTCCCTGE_AB95Da04_01_mgRes1_R.trim.f ATGTCGGGTCGTTGCCGGGATCGGACCGCGCTGGCGCGGTCCGGTTCCCT **************************************************gi|83627312|dbj|AB207867.1|_Es GACGACCGGGCCAACCGGATCAGAAATCCATGCCGCCCATGCCGCCCATAGE_AB95Da04_01_mgRes1_R.trim.f GACGACCGGGCCAACCGGATCAGAAATCCATGCCGCCCATGCCGCCCATA **************************************************gi|83627312|dbj|AB207867.1|_Es CCGCCAGCACCCGGCATGGCCGGCTCTTCCTTCTTCGGCACTTCGGCCACGE_AB95Da04_01_mgRes1_R.trim.f CCGCCAGCACCCGGCATGGCCGGCTCTTCCTTCTTCGGCACTTCGGCCAC **************************************************gi|83627312|dbj|AB207867.1|_Es GACCACTTCGGTCGTGATCGCAAGGCCGGCGACGGAAGCGGCGTGCTGCAGE_AB95Da04_01_mgRes1_R.trim.f GACCACTTCGGTCGTGATCGCAAGGCCGGCGACGGAAGCGGCGTGCTGCA **************************************************gi|83627312|dbj|AB207867.1|_Es GGGCCGAGCGGGTCACCTTGGTCGGGTCCAGGATGCCCATGGCGATCATGGE_AB95Da04_01_mgRes1_R.trim.f GGGCCGAGCGGGTCACCTTGGTCGGGTCCAGGATGCCCATGGCGATCATG **************************************************gi|83627312|dbj|AB207867.1|_Es TCGCCGAACTCGCCGGTGGCGGCGTTGTAGCCGTAGCTGCCTTCGCCGGCGE_AB95Da04_01_mgRes1_R.trim.f TCGCCGAACTCGCCGGTGGCGGCGTTGTAGCCGTAGCTGCCTTCGCCGGC **************************************************gi|83627312|dbj|AB207867.1|_Es CTTGACGTTGGCCACGATCACGCTCGGTTCTTCACCGGCGTTGGCCACGAGE_AB95Da04_01_mgRes1_R.trim.f CTTGACGTTGGCCACGATCACGCTCGGTTCTTCACCGGCGTTGGCCACGA **************************************************gi|83627312|dbj|AB207867.1|_Es TGGCGCGCAGCGGGGCTTCCAGCGCACGGCGGGTGATGGCGATGCCCAGGGE_AB95Da04_01_mgRes1_R.trim.f TGGCGCGCAGCGGGGCTTCCAGCGCACGGCGGGTGATGGCGATGCCCAGG **************************************************gi|83627312|dbj|AB207867.1|_Es TTCTGGTCTTCGTTGATGCCCTGCCAGGGCAGATCCGTGCACAGCACCTTGE_AB95Da04_01_mgRes1_R.trim.f TTCTGGTCTTCGTTGATGCCCTGCCAGGGCAGATCCGTGCACAGCACCTT **************************************************gi|83627312|dbj|AB207867.1|_Es GCCGTAGAAGAACAGCAAGGCCGCCAATGCCTGACGATGCGTGGAGACCGGE_AB95Da04_01_mgRes1_R.trim.f GCCGTAGAAGAACAGCAAGGCCGCCAATGCCTGACGATGCGTGGAGACCG **************************************************gi|83627312|dbj|AB207867.1|_Es AAACCTTGCGCTCGTTCGCCAGCCAGGACAGAAATGCCTCGACTTCGCTGGE_AB95Da04_01_mgRes1_R.trim.f AAACCTTGCGCTCGTTCGCCAGCCAGGACAGAAATGCCTCGACTTCGCTG **************************************************gi|83627312|dbj|AB207867.1|_Es CTGCCCAAGGTTGCCGGGTGACGCACACCGTGGAAACGGATGAAGGCACGGE_AB95Da04_01_mgRes1_R.trim.f CTGCCCAAGGTTGCCGGGTGACGCACACCGTGGAAACGGATGAAGGCACG **************************************************gi|83627312|dbj|AB207867.1|_Es AACCCAGTGGACATAAGCCTGTTCGGTTGGTAAGCTGTAATGCAAGTAGCGE_AB95Da04_01_mgRes1_R.trim.f AACCCAGTGGACATAAGCCT------------------------------ ******************** gi|83627312|dbj|AB207867.1|_Es TCCGGTGCGGGGACGGCTGCTCAGTGTTGCGCCTGTGTTCGCACGTTCGTGE_AB95Da04_01_mgRes1_R.trim.f ---------------------------------TCTGTTCGCACGTTCGT * ***************gi|83627312|dbj|AB207867.1|_Es ATCGGTGCGTTCTGATCTTCGCGTCAGACATTGCCGCGGCGCGGGCACAAGE_AB95Da04_01_mgRes1_R.trim.f ATCGGTGCGTTCTGATCTTCGCGTCAGACATTGCCGCGGCGCGGGCACAA **************************************************gi|83627312|dbj|AB207867.1|_Es CAAAAAGCCCGGCATCGCTGCCGGGCTCCGGCCCCGTCCTTGGGGCCTTGGE_AB95Da04_01_mgRes1_R.trim.f CAAAAAGCCCGGCATCGCTGCCGGGCTCCGGCCCCGTCCTTGGGGCCTTG **************************************************gi|83627312|dbj|AB207867.1|_Es ATGTCGGGTCGTTGCCGGGATCGGACCGCGCTGGCGCGGTCCGGTTCCCTGE_AB95Da04_01_mgRes1_R.trim.f ATGTCGGGTCGTTGCCGGGATCGGACCGCGCTGGCGCGGTCCGGTTCCCT **************************************************gi|83627312|dbj|AB207867.1|_Es GACGACCGGGCCAACCGGATCAGAAATCCATGCCGCCCATGCCGCCCATAGE_AB95Da04_01_mgRes1_R.trim.f GACGACCGGGCCAACCGGATCAGAAATCCATGCCGCCCATGCCGCCCATA **************************************************gi|83627312|dbj|AB207867.1|_Es CCGCCAGCACCCGGCATGGCCGGCTCTTCCTTCTTCGGCACTTCGGCCACGE_AB95Da04_01_mgRes1_R.trim.f CCGCCAGCACCCGGCATGGCCGGCTCTTCCTTCTTCGGCACTTCGGCCAC **************************************************gi|83627312|dbj|AB207867.1|_Es GACCACTTCGGTCGTGATCGCAAGGCCGGCGACGGAAGCGGCGTGCTGCAGE_AB95Da04_01_mgRes1_R.trim.f GACCACTTCGGTCGTGATCGCAAGGCCGGCGACGGAAGCGGCGTGCTGCA **************************************************gi|83627312|dbj|AB207867.1|_Es GGGCCGAGCGGGTCACCTTGGTCGGGTCCAGGATGCCCATGGCGATCATGGE_AB95Da04_01_mgRes1_R.trim.f GGGCCGAGCGGGTCACCTTGGTCGGGTCCAGGATGCCCATGGCGATCATG **************************************************gi|83627312|dbj|AB207867.1|_Es TCGCCGAACTCGCCGGTGGCGGCGTTGTAGCCGTAGCTGCCTTCGCCGGCGE_AB95Da04_01_mgRes1_R.trim.f TCGCCGAACTCGCCGGTGGCGGCGTTGTAGCCGTAGCTGCCTTCGCCGGC **************************************************gi|83627312|dbj|AB207867.1|_Es CTTGACGTTGGCCACGATCACGCTCGGTTCTTCACCGGCGTTGGCCACGAGE_AB95Da04_01_mgRes1_R.trim.f CTTGACGTTGGCCACGATCACGCTCGGTTCTTCACCGGCGTTGGCCACGA **************************************************gi|83627312|dbj|AB207867.1|_Es TGGCGCGCAGCGGGGCTTCCAGCGCACGGCGGGTGATGGCGATGCCCAGGGE_AB95Da04_01_mgRes1_R.trim.f TGGCGCGCAGCGGGGCTTCCAGCGCACGGCGGGTGATGGCGATGCCCAGG **************************************************gi|83627312|dbj|AB207867.1|_Es TTCTGGTCTTCGTTGATGCCCTGCCAGGGCAGATCCGTGCACAGCACCTTGE_AB95Da04_01_mgRes1_R.trim.f TTCTGGTCTTCGTTGATGCCCTGCCAGGGCAGATCCGTGCACAGCACCTT **************************************************gi|83627312|dbj|AB207867.1|_Es GCCGTAGAAGAACAGCAAGGCCGCCAATGCCTGACGATGCGTGGAGACCGGE_AB95Da04_01_mgRes1_R.trim.f GCCGTAGAAGAACAGCAAGGCCGCCAATGCCTGACGATGCGTGGAGACCG **************************************************gi|83627312|dbj|AB207867.1|_Es AAACCTTGCGCTCGTTCGCCAGCCAGGACAGAAATGCCTCGACTTCGCTGGE_AB95Da04_01_mgRes1_R.trim.f AAACCTTGCGCTCGTTCGCCAGCCAGGACAGAAATGCCTCGACTTCGCTG **************************************************gi|83627312|dbj|AB207867.1|_Es CTGCCCAAGGTTGCCGGGTGACGCACACCGTGGAAACGGATGAAGGCACGGE_AB95Da04_01_mgRes1_R.trim.f CTGCCCAAGGTTGCCGGGTGACGCACACCGTGGAAACGGATGAAGGCACG **************************************************gi|83627312|dbj|AB207867.1|_Es AACCCAGTGGACATAAGCCTGTTCGGTTGGTAAGCTGTAATGCAAGTAGCGE_AB95Da04_01_mgRes1_R.trim.f AACCCAGTGGACATAAGCCT------------------------------ ******************** Experiments by: G. Dantas, M. Sommer. Unpublished data >dbj|AB207867.1| Escherichia coli transposon Tn2610, complete sequence

  28. Experiments by: G. Dantas, M. Sommer. Unpublished data >gi|4583495|gb|AF133140.1| Pseudomonas sp. plasmid pPSTG2

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