Current Genetics

, Volume 63, Issue 6, pp 973–976 | Cite as

Fighting against evolution of antibiotic resistance by utilizing evolvable antimicrobial drugs

  • Mehmet Fatih Cansizoglu
  • Erdal Toprak


Antibiotic resistance is a worldwide public health problem (Bush et al. in Nat Rev Microbiol 9:894–896, 2011). The lack of effective therapies against resistant bacteria globally leads to prolonged treatments, increased mortality, and inflating health care costs (Oz et al. in Mol Biol Evol 31:2387–2401, 2014; Martinez in Science 321:365–367, 2008; Lipsitch et al. in Proc Natl Acad Sci USA 97:1938–1943, 2000; Taubes in Science 321:356–361, 2008; Laxminarayan et al. in Lancet, 2016; Laxminarayan et al. in Lancet Infect Dis 13:1057–1098, 2013). Current efforts towards a solution of this problem can be boiled down to two main strategies: (1) developing of new antimicrobial agents and (2) searching for smart strategies that can restore or preserve the efficacy of existing antimicrobial agents. In this short review article, we discuss the need for evolvable antimicrobial agents, focusing on a new antimicrobial technology that utilizes peptide-conjugated phosphorodiamidate morpholino oligomers to inhibit the growth of pathogenic bacteria by targeting bacterial genes.


Antibiotic resistance Evolution Microbial evolution Gene silencing Peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs) 



Authors would like to thank Dr. Miriam Osterfield for her careful and critical reading of the manuscript.


  1. Ayhan DH et al (2016) Sequence-specific targeting of bacterial resistance genes increases antibiotic efficacy. PLoS Biol 14(9):e1002552CrossRefPubMedPubMedCentralGoogle Scholar
  2. Baba T et al (2006) Construction of Escherichia coli K-12 in-frame, single-gene knockout mutants: the Keio collection. Mol Syst Biol 2:2006.0008CrossRefPubMedPubMedCentralGoogle Scholar
  3. Baym M, Stone LK, Kishony R (2016) Multidrug evolutionary strategies to reverse antibiotic resistance. Science 351(6268):3292CrossRefGoogle Scholar
  4. Bergstrom CT, Lo M, Lipsitch M (2004) Ecological theory suggests that antimicrobial cycling will not reduce antimicrobial resistance in hospitals. Proc Natl Acad Sci USA 101(36):13285–13290CrossRefPubMedPubMedCentralGoogle Scholar
  5. Bikard D et al (2013) Programmable repression and activation of bacterial gene expression using an engineered CRISPR-Cas system. Nucleic Acids Res 41(15):7429–7437CrossRefPubMedPubMedCentralGoogle Scholar
  6. Blair JM et al (2015) AcrB drug-binding pocket substitution confers clinically relevant resistance and altered substrate specificity. Proc Natl Acad Sci USA 112(11):3511–3516CrossRefPubMedPubMedCentralGoogle Scholar
  7. Blair JM, Richmond GE, Piddock LJ (2014) Multidrug efflux pumps in Gram-negative bacteria and their role in antibiotic resistance. Future Microbiol 9(10):1165–1177CrossRefPubMedGoogle Scholar
  8. Brinsmade SR (2016) CodY, a master integrator of metabolism and virulence in Gram-positive bacteria. Curr Genet 63(3):417–425. doi: 10.1007/s00294-016-0656-5 CrossRefPubMedGoogle Scholar
  9. Bush K et al (2011) Tackling antibiotic resistance. Nat Rev Microbiol 9(12):894–896CrossRefPubMedPubMedCentralGoogle Scholar
  10. Datsenko KA, Wanner BL (2000) One-step inactivation of chromosomal genes in Escherichia coli K-12 using PCR products. Proc Natl Acad Sci USA 97(12):6640–6645CrossRefPubMedPubMedCentralGoogle Scholar
  11. Geller BL et al (2005) Antisense phosphorodiamidate morpholino oligomer inhibits viability of Escherichia coli in pure culture and in mouse peritonitis. J Antimicrob Chemother 55(6):983–988CrossRefPubMedGoogle Scholar
  12. Geller BL et al (2013) Gene-silencing antisense oligomers inhibit acinetobacter growth in vitro and in vivo. J Infect Dis 208(10):1553–1560CrossRefPubMedPubMedCentralGoogle Scholar
  13. Gonzales PR et al (2015) Synergistic, collaterally sensitive beta-lactam combinations suppress resistance in MRSA. Nat Chem Biol 11(11):855–861CrossRefPubMedPubMedCentralGoogle Scholar
  14. Greenberg DE et al (2010) Antisense phosphorodiamidate morpholino oligomers targeted to an essential gene inhibit Burkholderia cepacia complex. J Infect Dis 201(12):1822–1830CrossRefPubMedPubMedCentralGoogle Scholar
  15. Hegreness M et al (2008) Accelerated evolution of resistance in multidrug environments. Proc Natl Acad Sci USA 105(37):13977–13981CrossRefPubMedPubMedCentralGoogle Scholar
  16. Howard JJ et al (2017) Inhibition of pseudomonas aeruginosa by peptide-conjugated phosphorodiamidate morpholino oligomers. Antimicrob Agents Chemother 61(4):e01938-16CrossRefPubMedPubMedCentralGoogle Scholar
  17. Laabei M, Massey R (2016) Using functional genomics to decipher the complexity of microbial pathogenicity. Curr Genet 62(3):523–525CrossRefPubMedPubMedCentralGoogle Scholar
  18. Laxminarayan R et al (2013) Antibiotic resistance-the need for global solutions. Lancet Infect Dis 13(12):1057–1098CrossRefPubMedGoogle Scholar
  19. Laxminarayan R et al (2016) Access to effective antimicrobials: a worldwide challenge. Lancet 387(10014):168–175CrossRefPubMedGoogle Scholar
  20. Lipsitch M, Bergstrom CT, Levin BR (2000) The epidemiology of antibiotic resistance in hospitals: paradoxes and prescriptions. Proc Natl Acad Sci USA 97(4):1938–1943CrossRefPubMedPubMedCentralGoogle Scholar
  21. Martinez JL (2008) Antibiotics and antibiotic resistance genes in natural environments. Science 321(5887):365–367CrossRefPubMedGoogle Scholar
  22. Meng J et al (2015) Reversion of antibiotic resistance by inhibiting mecA in clinical methicillin-resistant Staphylococci by antisense phosphorothioate oligonucleotide. J Antibiot (Tokyo) 68(3):158–164CrossRefGoogle Scholar
  23. Nichols RJ et al (2011) Phenotypic landscape of a bacterial cell. Cell 144(1):143–156CrossRefPubMedGoogle Scholar
  24. Orndorff PE (2016) Use of bacteriophage to target bacterial surface structures required for virulence: a systematic search for antibiotic alternatives. Curr Genet 62(4):753–757CrossRefPubMedPubMedCentralGoogle Scholar
  25. Oz T et al (2014) Strength of selection pressure is an important parameter contributing to the complexity of antibiotic resistance evolution. Mol Biol Evol 31(9):2387–2401CrossRefPubMedPubMedCentralGoogle Scholar
  26. Sontheimer EJ, Marraffini LA (2010) Microbiology: slicer for DNA. Nature 468(7320):45–46CrossRefPubMedPubMedCentralGoogle Scholar
  27. Taubes G (2008) The bacteria fight back. Science 321(5887):356–361CrossRefPubMedGoogle Scholar
  28. Tilley LD et al (2006) Gene-specific effects of antisense phosphorodiamidate morpholino oligomer-peptide conjugates on Escherichia coli and Salmonella enterica serovar typhimurium in pure culture and in tissue culture. Antimicrob Agents Chemother 50(8):2789–2796CrossRefPubMedPubMedCentralGoogle Scholar
  29. Tilley LD et al (2007) Antisense peptide-phosphorodiamidate morpholino oligomer conjugate: dose-response in mice infected with Escherichia coli. J Antimicrob Chemother 59(1):66–73CrossRefPubMedGoogle Scholar
  30. Toprak E et al (2012) Evolutionary paths to antibiotic resistance under dynamically sustained drug selection. Nat Genet 44(1):101–105CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  1. 1.Green Center for Systems BiologyUniversity of Texas Southwestern Medical CenterDallasUSA
  2. 2.Department of PharmacologyUniversity of Texas Southwestern Medical CenterDallasUSA

Personalised recommendations