Skip to main content
PMC home page
Comparative and Functional Genomics logoLink to Comparative and Functional Genomics
. 2004 Jun;5(4):304–327. doi: 10.1002/cfg.411

Comparative Genomic Assessment of Novel Broad-Spectrum Targets for Antibacterial Drugs

Thomas A White 1, Douglas B Kell 2,✉
PMCID: PMC2447455  PMID: 18629165

Abstract

Single and multiple resistance to antibacterial drugs currently in use is spreading, since they act against only a very small number of molecular targets; finding novel targets for anti-infectives is therefore of great importance. All protein sequences from three pathogens (Staphylococcus aureus, Mycobacterium tuberculosis and Escherichia coli O157:H7 EDL993) were assessed via comparative genomics methods for their suitability as antibacterial targets according to a number of criteria, including the essentiality of the protein, its level of sequence conservation, and its distribution in pathogens, bacteria and eukaryotes (especially humans). Each protein was scored and ranked based on weighted variants of these criteria in order to prioritize proteins as potential novel broad-spectrum targets for antibacterial drugs. A number of proteins proved to score highly in all three species and were robust to variations in the scoring system used. Sensitivity analysis indicated the quantitative contribution of each metric to the overall score. After further analysis of these targets, tRNA methyltransferase (trmD) and translation initiation factor IF-1 (infA) emerged as potential and novel antimicrobial targets very worthy of further investigation. The scoring strategy used might be of value in other areas of post-genomic drug discovery.

Full Text

The Full Text of this article is available as a PDF (1.7 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ahn Hyung Jun, Kim Hyeon-Woo, Yoon Hye-Jin, Lee Byung Il, Suh Se Won, Yang Jin Kuk. Crystal structure of tRNA(m1G37)methyltransferase: insights into tRNA recognition. EMBO J. 2003 Jun 2;22(11):2593–2603. doi: 10.1093/emboj/cdg269. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Alksne Lefa E. Virulence as a target for antimicrobial chemotherapy. Expert Opin Investig Drugs. 2002 Aug;11(8):1149–1159. doi: 10.1517/13543784.11.8.1149. [DOI] [PubMed] [Google Scholar]
  3. Allsop A. E. New antibiotic discovery, novel screens, novel targets and impact of microbial genomics. Curr Opin Microbiol. 1998 Oct;1(5):530–534. doi: 10.1016/s1369-5274(98)80085-4. [DOI] [PubMed] [Google Scholar]
  4. Allsop A., Illingworth R. The impact of genomics and related technologies on the search for new antibiotics. J Appl Microbiol. 2002;92(1):7–12. doi: 10.1046/j.1365-2672.2002.01483.x. [DOI] [PubMed] [Google Scholar]
  5. Altschul S. F., Gish W., Miller W., Myers E. W., Lipman D. J. Basic local alignment search tool. J Mol Biol. 1990 Oct 5;215(3):403–410. doi: 10.1016/S0022-2836(05)80360-2. [DOI] [PubMed] [Google Scholar]
  6. Altschul S. F., Madden T. L., Schäffer A. A., Zhang J., Zhang Z., Miller W., Lipman D. J. Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res. 1997 Sep 1;25(17):3389–3402. doi: 10.1093/nar/25.17.3389. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Brunder W., Khan A. S., Hacker J., Karch H. Novel type of fimbriae encoded by the large plasmid of sorbitol-fermenting enterohemorrhagic Escherichia coli O157:H(-). Infect Immun. 2001 Jul;69(7):4447–4457. doi: 10.1128/IAI.69.7.4447-4457.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Buysse J. M. The role of genomics in antibacterial target discovery. Curr Med Chem. 2001 Dec;8(14):1713–1726. doi: 10.2174/0929867013371699. [DOI] [PubMed] [Google Scholar]
  9. Chittum H. S., Champney W. S. Erythromycin inhibits the assembly of the large ribosomal subunit in growing Escherichia coli cells. Curr Microbiol. 1995 May;30(5):273–279. doi: 10.1007/BF00295501. [DOI] [PubMed] [Google Scholar]
  10. Chopra I., Hesse L., O'Neill A. J. Exploiting current understanding of antibiotic action for discovery of new drugs. J Appl Microbiol. 2002;92 (Suppl):4S–15S. [PubMed] [Google Scholar]
  11. Cummings H. S., Hershey J. W. Translation initiation factor IF1 is essential for cell viability in Escherichia coli. J Bacteriol. 1994 Jan;176(1):198–205. doi: 10.1128/jb.176.1.198-205.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Dahlquist K. D., Puglisi J. D. Interaction of translation initiation factor IF1 with the E. coli ribosomal A site. J Mol Biol. 2000 May 26;299(1):1–15. doi: 10.1006/jmbi.2000.3672. [DOI] [PubMed] [Google Scholar]
  13. Davies J. Inactivation of antibiotics and the dissemination of resistance genes. Science. 1994 Apr 15;264(5157):375–382. doi: 10.1126/science.8153624. [DOI] [PubMed] [Google Scholar]
  14. Dougherty Thomas J., Barrett John F., Pucci Michael J. Microbial genomics and novel antibiotic discovery: new technology to search for new drugs. Curr Pharm Des. 2002;8(13):1119–1135. doi: 10.2174/1381612023394782. [DOI] [PubMed] [Google Scholar]
  15. Dunman P. M., Murphy E., Haney S., Palacios D., Tucker-Kellogg G., Wu S., Brown E. L., Zagursky R. J., Shlaes D., Projan S. J. Transcription profiling-based identification of Staphylococcus aureus genes regulated by the agr and/or sarA loci. J Bacteriol. 2001 Dec;183(24):7341–7353. doi: 10.1128/JB.183.24.7341-7353.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Egebjerg J., Douthwaite S., Garrett R. A. Antibiotic interactions at the GTPase-associated centre within Escherichia coli 23S rRNA. EMBO J. 1989 Feb;8(2):607–611. doi: 10.1002/j.1460-2075.1989.tb03415.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. El Zoeiby Ahmed, Sanschagrin François, Levesque Roger C. Structure and function of the Mur enzymes: development of novel inhibitors. Mol Microbiol. 2003 Jan;47(1):1–12. doi: 10.1046/j.1365-2958.2003.03289.x. [DOI] [PubMed] [Google Scholar]
  18. Forsyth R. Allyn, Haselbeck Robert J., Ohlsen Kari L., Yamamoto Robert T., Xu Howard, Trawick John D., Wall Daniel, Wang Liangsu, Brown-Driver Vickie, Froelich Jamie M. A genome-wide strategy for the identification of essential genes in Staphylococcus aureus. Mol Microbiol. 2002 Mar;43(6):1387–1400. doi: 10.1046/j.1365-2958.2002.02832.x. [DOI] [PubMed] [Google Scholar]
  19. Giaever G., Shoemaker D. D., Jones T. W., Liang H., Winzeler E. A., Astromoff A., Davis R. W. Genomic profiling of drug sensitivities via induced haploinsufficiency. Nat Genet. 1999 Mar;21(3):278–283. doi: 10.1038/6791. [DOI] [PubMed] [Google Scholar]
  20. Glass John I., Belanger Aimee E., Robertson Gregory T. Streptococcus pneumoniae as a genomics platform for broad-spectrum antibiotic discovery. Curr Opin Microbiol. 2002 Jun;5(3):338–342. doi: 10.1016/s0959-4388(02)90328-4. [DOI] [PubMed] [Google Scholar]
  21. Gribskov M. Translational initiation factors IF-1 and eIF-2 alpha share an RNA-binding motif with prokaryotic ribosomal protein S1 and polynucleotide phosphorylase. Gene. 1992 Sep 21;119(1):107–111. doi: 10.1016/0378-1119(92)90073-x. [DOI] [PubMed] [Google Scholar]
  22. Haney Steven A., Alksne Lefa E., Dunman Paul M., Murphy Ellen, Projan Steven J. Genomics in anti-infective drug discovery--getting to endgame. Curr Pharm Des. 2002;8(13):1099–1118. doi: 10.2174/1381612023394845. [DOI] [PubMed] [Google Scholar]
  23. Heinemann JA. How antibiotics cause antibiotic resistance. Drug Discov Today. 1999 Feb;4(2):72–79. doi: 10.1016/s1359-6446(98)01294-x. [DOI] [PubMed] [Google Scholar]
  24. Hoffmaster A. R., Koehler T. M. Control of virulence gene expression in Bacillus anthracis. J Appl Microbiol. 1999 Aug;87(2):279–281. doi: 10.1046/j.1365-2672.1999.00887.x. [DOI] [PubMed] [Google Scholar]
  25. Hopkins Andrew L., Groom Colin R. The druggable genome. Nat Rev Drug Discov. 2002 Sep;1(9):727–730. doi: 10.1038/nrd892. [DOI] [PubMed] [Google Scholar]
  26. Inoue R., Kaito C., Tanabe M., Kamura K., Akimitsu N., Sekimizu K. Genetic identification of two distinct DNA polymerases, DnaE and PolC, that are essential for chromosomal DNA replication in Staphylococcus aureus. Mol Genet Genomics. 2001 Aug 16;266(4):564–571. doi: 10.1007/s004380100564. [DOI] [PubMed] [Google Scholar]
  27. Isaacson Richard E. Genomics and the prospects for the discovery of new targets for antibacterial and antifungal agents. Curr Pharm Des. 2002;8(13):1091–1098. doi: 10.2174/1381612023394764. [DOI] [PubMed] [Google Scholar]
  28. Ji Yinduo. The role of genomics in the discovery of novel targets for antibiotic therapy. Pharmacogenomics. 2002 May;3(3):315–323. doi: 10.1517/14622416.3.3.315. [DOI] [PubMed] [Google Scholar]
  29. Kell Douglas B., Oliver Stephen G. Here is the evidence, now what is the hypothesis? The complementary roles of inductive and hypothesis-driven science in the post-genomic era. Bioessays. 2004 Jan;26(1):99–105. doi: 10.1002/bies.10385. [DOI] [PubMed] [Google Scholar]
  30. Knowles D. J., King F. The impact of bacterial genomics on antibacterial discovery. Adv Exp Med Biol. 1998;456:183–195. doi: 10.1007/978-1-4615-4897-3_10. [DOI] [PubMed] [Google Scholar]
  31. Kobayashi K., Ehrlich S. D., Albertini A., Amati G., Andersen K. K., Arnaud M., Asai K., Ashikaga S., Aymerich S., Bessieres P. Essential Bacillus subtilis genes. Proc Natl Acad Sci U S A. 2003 Apr 7;100(8):4678–4683. doi: 10.1073/pnas.0730515100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Koehler T. M. Bacillus anthracis genetics and virulence gene regulation. Curr Top Microbiol Immunol. 2002;271:143–164. doi: 10.1007/978-3-662-05767-4_7. [DOI] [PubMed] [Google Scholar]
  33. Kornder J. D. Streptomycin revisited: molecular action in the microbial cell. Med Hypotheses. 2002 Jan;58(1):34–46. doi: 10.1054/mehy.2001.1450. [DOI] [PubMed] [Google Scholar]
  34. Kumar S., Tamura K., Jakobsen I. B., Nei M. MEGA2: molecular evolutionary genetics analysis software. Bioinformatics. 2001 Dec;17(12):1244–1245. doi: 10.1093/bioinformatics/17.12.1244. [DOI] [PubMed] [Google Scholar]
  35. Lin A. H., Murray R. W., Vidmar T. J., Marotti K. R. The oxazolidinone eperezolid binds to the 50S ribosomal subunit and competes with binding of chloramphenicol and lincomycin. Antimicrob Agents Chemother. 1997 Oct;41(10):2127–2131. doi: 10.1128/aac.41.10.2127. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Lipinski C. A., Lombardo F., Dominy B. W., Feeney P. J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev. 2001 Mar 1;46(1-3):3–26. doi: 10.1016/s0169-409x(00)00129-0. [DOI] [PubMed] [Google Scholar]
  37. McDevitt D., Rosenberg M. Exploiting genomics to discover new antibiotics. Trends Microbiol. 2001 Dec;9(12):611–617. doi: 10.1016/s0966-842x(01)02235-1. [DOI] [PubMed] [Google Scholar]
  38. Mjolsness E., DeCoste D. Machine learning for science: state of the art and future prospects. Science. 2001 Sep 14;293(5537):2051–2055. doi: 10.1126/science.293.5537.2051. [DOI] [PubMed] [Google Scholar]
  39. Oneyama Chitose, Nakano Hirofumi, Sharma Sreenath V. UCS15A, a novel small molecule, SH3 domain-mediated protein-protein interaction blocking drug. Oncogene. 2002 Mar 27;21(13):2037–2050. doi: 10.1038/sj.onc.1205271. [DOI] [PubMed] [Google Scholar]
  40. Paulmurugan Ramasamy, Massoud Tarik F., Huang Jing, Gambhir Sanjiv S. Molecular imaging of drug-modulated protein-protein interactions in living subjects. Cancer Res. 2004 Mar 15;64(6):2113–2119. doi: 10.1158/0008-5472.can-03-2972. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Payne D. J., Holmes D. J., Rosenberg M. Delivering novel targets and antibiotics from genomics. Curr Opin Investig Drugs. 2001 Aug;2(8):1028–1034. [PubMed] [Google Scholar]
  42. Payne D. J., Warren P. V., Holmes D. J., Ji Y., Lonsdale J. T. Bacterial fatty-acid biosynthesis: a genomics-driven target for antibacterial drug discovery. Drug Discov Today. 2001 May 1;6(10):537–544. doi: 10.1016/s1359-6446(01)01774-3. [DOI] [PubMed] [Google Scholar]
  43. Projan Steven J. New (and not so new) antibacterial targets - from where and when will the novel drugs come? Curr Opin Pharmacol. 2002 Oct;2(5):513–522. doi: 10.1016/s1471-4892(02)00197-2. [DOI] [PubMed] [Google Scholar]
  44. Sassetti Christopher M., Boyd Dana H., Rubin Eric J. Genes required for mycobacterial growth defined by high density mutagenesis. Mol Microbiol. 2003 Apr;48(1):77–84. doi: 10.1046/j.1365-2958.2003.03425.x. [DOI] [PubMed] [Google Scholar]
  45. Schmid M. B. Novel approaches to the discovery of antimicrobial agents. Curr Opin Chem Biol. 1998 Aug;2(4):529–534. doi: 10.1016/s1367-5931(98)80130-0. [DOI] [PubMed] [Google Scholar]
  46. Schnappinger D., Hillen W. Tetracyclines: antibiotic action, uptake, and resistance mechanisms. Arch Microbiol. 1996 Jun;165(6):359–369. doi: 10.1007/s002030050339. [DOI] [PubMed] [Google Scholar]
  47. Sharma Vijay K., Dean-Nystrom Evelyn A. Detection of enterohemorrhagic Escherichia coli O157:H7 by using a multiplex real-time PCR assay for genes encoding intimin and Shiga toxins. Vet Microbiol. 2003 May 29;93(3):247–260. doi: 10.1016/s0378-1135(03)00039-7. [DOI] [PubMed] [Google Scholar]
  48. Spaltmann F, Blunck M, Ziegelbauer K. Computer-aided target selection-prioritizing targets for antifungal drug discovery. Drug Discov Today. 1999 Jan;4(1):17–26. doi: 10.1016/s1359-6446(98)01278-1. [DOI] [PubMed] [Google Scholar]
  49. Stephenson K., Hoch J. A. Developing inhibitors to selectively target two-component and phosphorelay signal transduction systems of pathogenic microorganisms. Curr Med Chem. 2004 Mar;11(6):765–773. doi: 10.2174/0929867043455765. [DOI] [PubMed] [Google Scholar]
  50. Stephenson Keith, Hoch James A. Two-component and phosphorelay signal-transduction systems as therapeutic targets. Curr Opin Pharmacol. 2002 Oct;2(5):507–512. doi: 10.1016/s1471-4892(02)00194-7. [DOI] [PubMed] [Google Scholar]
  51. Struelens M. J. The epidemiology of antimicrobial resistance in hospital acquired infections: problems and possible solutions. BMJ. 1998 Sep 5;317(7159):652–654. doi: 10.1136/bmj.317.7159.652. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Stuber Katja, Frey Joachim, Burnens André P., Kuhnert Peter. Detection of type III secretion genes as a general indicator of bacterial virulence. Mol Cell Probes. 2003 Feb;17(1):25–32. doi: 10.1016/s0890-8508(02)00108-1. [DOI] [PubMed] [Google Scholar]
  53. Sun Y. H., Bakshi S., Chalmers R., Tang C. M. Functional genomics of Neisseria meningitidis pathogenesis. Nat Med. 2000 Nov;6(11):1269–1273. doi: 10.1038/81380. [DOI] [PubMed] [Google Scholar]
  54. Tanner Martin E., Vaganay Sabine, van Heijenoort Jean, Blanot Didier. Phosphinate Inhibitors of the D-Glutamic Acid-Adding Enzyme of Peptidoglycan Biosynthesis. J Org Chem. 1996 Mar 8;61(5):1756–1760. doi: 10.1021/jo951780a. [DOI] [PubMed] [Google Scholar]
  55. Terstappen G. C., Reggiani A. In silico research in drug discovery. Trends Pharmacol Sci. 2001 Jan;22(1):23–26. doi: 10.1016/s0165-6147(00)01584-4. [DOI] [PubMed] [Google Scholar]
  56. Thompson J. D., Gibson T. J., Plewniak F., Jeanmougin F., Higgins D. G. The CLUSTAL_X windows interface: flexible strategies for multiple sequence alignment aided by quality analysis tools. Nucleic Acids Res. 1997 Dec 15;25(24):4876–4882. doi: 10.1093/nar/25.24.4876. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Triccas J. A., Gicquel B. Life on the inside: probing mycobacterium tuberculosis gene expression during infection. Immunol Cell Biol. 2000 Aug;78(4):311–317. doi: 10.1046/j.1440-1711.2000.00934.x. [DOI] [PubMed] [Google Scholar]
  58. Wang Gehua, Clark Clifford G., Rodgers Frank G. Detection in Escherichia coli of the genes encoding the major virulence factors, the genes defining the O157:H7 serotype, and components of the type 2 Shiga toxin family by multiplex PCR. J Clin Microbiol. 2002 Oct;40(10):3613–3619. doi: 10.1128/JCM.40.10.3613-3619.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Weber W., Anke T., Bross M., Steglich W. Strobilurin D and strobilurin F: two new cytostatic and antifungal (E)-beta-methoxyacrylate antibiotics from Cyphellopsis anomala (1). Planta Med. 1990 Oct;56(5):446–450. doi: 10.1055/s-2006-961008. [DOI] [PubMed] [Google Scholar]
  60. Willins Debra Aker, Kessler Marco, Walker Scott S., Reyes Gregory R., Cottarel Guillaume. Genomics strategies for antifungal drug discovery--from gene discovery to compound screening. Curr Pharm Des. 2002;8(13):1137–1154. doi: 10.2174/1381612023394890. [DOI] [PubMed] [Google Scholar]
  61. Zambrowicz Brian P., Sands Arthur T. Knockouts model the 100 best-selling drugs--will they model the next 100? Nat Rev Drug Discov. 2003 Jan;2(1):38–51. doi: 10.1038/nrd987. [DOI] [PubMed] [Google Scholar]

Articles from Comparative and Functional Genomics are provided here courtesy of Wiley

RESOURCES