Abstract
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.
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References
Ayhan DH et al (2016) Sequence-specific targeting of bacterial resistance genes increases antibiotic efficacy. PLoS Biol 14(9):e1002552
Baba T et al (2006) Construction of Escherichia coli K-12 in-frame, single-gene knockout mutants: the Keio collection. Mol Syst Biol 2:2006.0008
Baym M, Stone LK, Kishony R (2016) Multidrug evolutionary strategies to reverse antibiotic resistance. Science 351(6268):3292
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):13285–13290
Bikard D et al (2013) Programmable repression and activation of bacterial gene expression using an engineered CRISPR-Cas system. Nucleic Acids Res 41(15):7429–7437
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):3511–3516
Blair JM, Richmond GE, Piddock LJ (2014) Multidrug efflux pumps in Gram-negative bacteria and their role in antibiotic resistance. Future Microbiol 9(10):1165–1177
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
Bush K et al (2011) Tackling antibiotic resistance. Nat Rev Microbiol 9(12):894–896
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):6640–6645
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):983–988
Geller BL et al (2013) Gene-silencing antisense oligomers inhibit acinetobacter growth in vitro and in vivo. J Infect Dis 208(10):1553–1560
Gonzales PR et al (2015) Synergistic, collaterally sensitive beta-lactam combinations suppress resistance in MRSA. Nat Chem Biol 11(11):855–861
Greenberg DE et al (2010) Antisense phosphorodiamidate morpholino oligomers targeted to an essential gene inhibit Burkholderia cepacia complex. J Infect Dis 201(12):1822–1830
Hegreness M et al (2008) Accelerated evolution of resistance in multidrug environments. Proc Natl Acad Sci USA 105(37):13977–13981
Howard JJ et al (2017) Inhibition of pseudomonas aeruginosa by peptide-conjugated phosphorodiamidate morpholino oligomers. Antimicrob Agents Chemother 61(4):e01938-16
Laabei M, Massey R (2016) Using functional genomics to decipher the complexity of microbial pathogenicity. Curr Genet 62(3):523–525
Laxminarayan R et al (2013) Antibiotic resistance-the need for global solutions. Lancet Infect Dis 13(12):1057–1098
Laxminarayan R et al (2016) Access to effective antimicrobials: a worldwide challenge. Lancet 387(10014):168–175
Lipsitch M, Bergstrom CT, Levin BR (2000) The epidemiology of antibiotic resistance in hospitals: paradoxes and prescriptions. Proc Natl Acad Sci USA 97(4):1938–1943
Martinez JL (2008) Antibiotics and antibiotic resistance genes in natural environments. Science 321(5887):365–367
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):158–164
Nichols RJ et al (2011) Phenotypic landscape of a bacterial cell. Cell 144(1):143–156
Orndorff PE (2016) Use of bacteriophage to target bacterial surface structures required for virulence: a systematic search for antibiotic alternatives. Curr Genet 62(4):753–757
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):2387–2401
Sontheimer EJ, Marraffini LA (2010) Microbiology: slicer for DNA. Nature 468(7320):45–46
Taubes G (2008) The bacteria fight back. Science 321(5887):356–361
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):2789–2796
Tilley LD et al (2007) Antisense peptide-phosphorodiamidate morpholino oligomer conjugate: dose-response in mice infected with Escherichia coli. J Antimicrob Chemother 59(1):66–73
Toprak E et al (2012) Evolutionary paths to antibiotic resistance under dynamically sustained drug selection. Nat Genet 44(1):101–105
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Authors would like to thank Dr. Miriam Osterfield for her careful and critical reading of the manuscript.
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Communicated by M. Kupiec.
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Cansizoglu, M.F., Toprak, E. Fighting against evolution of antibiotic resistance by utilizing evolvable antimicrobial drugs. Curr Genet 63, 973–976 (2017). https://doi.org/10.1007/s00294-017-0703-x
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DOI: https://doi.org/10.1007/s00294-017-0703-x