Aptamers in the Treatment of Bacterial Infections: Problems and Prospects

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Aptamers are short single-stranded oligonucleotides which are selected via targeted chemical evolution in vitro to bind a molecular target of interest. The aptamer selection technology is designated as SELEX (Systematic evolution of ligands by exponential enrichment). SELEX enables isolation of oligonucleotide aptamers binding a wide range of targets of interest with little respect for their nature and molecular weight. A number of applications of aptamer selection were developed ranging from biosensor technologies to antitumor drug discovery. First aptamer-based pharmaceutical (Macugen) was approved by FDA for clinical use in 2004, and since then more than ten aptamer-based drugs undergo various phases of clinical trials. From the medicinal chemist’s point of view, aptamers represent a new class of molecules suitable for the development of new therapeutics. Due to the stability, relative synthesis simplicity, and development of advanced strategies of target specific molecular selection, aptamers attract increased attention of drug discovery community. Difficulties of the development of next-generation antibiotics basing on the conventional basis of combinatorial chemistry and high-throughput screening have also amplified the interest to aptamer-based therapeutic candidates. The present article reviews the investigations focused on the development of antibacterial aptamers and discusses the potential and current limitations of the use of this type of therapeutic molecules.

About the authors

N. A. Zeninskaya

State Research Center for Applied Microbiology and Biotechnology

Email: nataliazeninskaya@mail.ru
ORCID iD: 0000-0002-5388-292X
Obolensk Russian Federation

A. V. Kolesnikov

State Research Center for Applied Microbiology and Biotechnology;
Immunological Engineering Institution

Email: pfu2000@mail.ru
ORCID iD: 0000-0001-8108-0265



Russian Federation

A. K. Ryabko

State Research Center for Applied Microbiology and Biotechnology

Email: ryabko_alena@mail.ru
ORCID iD: 0000-0001-7478-909X
Obolensk Russian Federation

I. G. Shemyakin

State Research Center for Applied Microbiology and Biotechnology

Email: shemyakin@obolensk.org
ORCID iD: 0000-0001-9667-1674
Obolensk Russian Federation

I. A. Dyatlov

State Research Center for Applied Microbiology and Biotechnology

Author for correspondence.
Email: dyatlov@obolensk.org
ORCID iD: 0000-0003-1078-4585

A. V. Kozyr

State Research Center for Applied Microbiology and Biotechnology

Email: avkozyr@gmail.com
ORCID iD: 0000-0001-6295-5943
Obolensk Russian Federation


  1. Klussmann S, editor. The aptamer handbook: functional oligonucleotides and their applications. Weinheim: Wiley-VCH; 2006. doi: 10.1002/3527608192.
  2. Tan W, Fang X, editors. Aptamers selected by cell-SELEX for theranostics. Berlin: Springer-Verlag Berlin Heidelberg; 2015. 352 p. doi: 10.1007/978-3-662-46226-3.
  3. Ptashne M, Hopkins N. The operators controlled by the lambda phage repressor. Proc Natl Acad Sci U S A. 1968;60(4):1282–1287. doi: 10.1073/pnas.60.4.1282.
  4. Westhof E. Isostericity and tautomerism of base pairs in nucleic acids. FEBS Lett. 2014;588(15):2464–2469. doi: 10.1016/j. febslet.2014.06.031.
  5. Cech TR. Ribozymes, the first 20 years. Biochem Soc Trans. 2002;30(6):1162–1166. doi: 10.1042/bst0301162.
  6. Silverman SK. Catalytic DNA: scope, applications, and biochemistry of deoxyribozyme. Trends Biochem Sci. 2016;41(7):595–609. doi: 10.1016/j.tibs.2016.04.010.
  7. Ellington AD, Szostak JW. In vitro selection of RNA molecules that bind specific ligands. Nature. 1990;346(6287):818–822. doi: 10.1038/346818a0.
  8. Tuerk C, Gold L. Systematic evolution of ligands by exponential enrichment: RNA ligands to bacteriophage T4 DNA polymerase. Science. 1990;249(4968):505–510. doi: 10.1126/science.2200121.
  9. FDA orders new phase III trial for anticancer drug; SuperGen withdraws orathecin NDA; FDA okays keratinocyte growth factor for prevention of mucositis during chemotherapy; AstraZeneca withdraws application for European approval of Iressa; FDA approves anti-angiogenesis agent for “wet” age-related macular degeneration; Access pharmaceuticals gets clearance for clinical trials of AP5346; FDA establishes nanotechnology site; Microarray chip for genetic analysis receives FDA clearance. Biotechnol Law Rep. 2005;24(2):177–179. doi: 10.1089/blr.2005.24.177.
  10. Weinberg MS. Therapeutic Aptamers March On. Mol Ther Nucleic Acids. 2014;3(9):e194. doi: 10.1038/mtna.2014.46
  11. Blind M, Blank M. Aptamer selection technology and recent advances. Mol Ther Nucleic Acids. 2015;4(1):e223. doi: 10.1038/ mtna.2014.74.
  12. Ozer A, Pagano JM, Lis JT. New technologies provide quantum changes in the scale, speed, and success of SELEX methods and aptamer characterization. Mol Ther Nucleic Acids. 2014;3(8):e183. doi: 10.1038/mtna.2014.34.
  13. Schutze T, Wilhelm B, Greiner N, et al. Probing the SELEX process with next-generation sequencing. PLoS One. 2011;6(12):e29604. doi: 10.1371/journal.pone.0029604.
  14. Hicke BJ, Stephens AW. Escort aptamers: a delivery service for diagnosis and therapy. J Clin Invest. 2000;106(8):923–928. doi: 10.1172/JCI11324.
  15. Sun H, Zu Y. Aptamers and their applications in nanomedicine. Small. 2015;11(20):2352–2364. doi: 10.1002/smll.201403073.
  16. Keefe AD, Pai S, Ellington A. Aptamers as therapeutics. Nat Rev Drug Discov. 2010;9(7):537–550. doi: 10.1038/nrd3141.
  17. Nimjee SM, Rusconi CP, Sullenger BA. Aptamers: an emerging class of therapeutics. Annu Rev Med. 2005;56(1):555–583. doi: 10.1146/annurev.med.56.062904.144915.
  18. Thiel KW, Giangrande PH. Therapeutic applications of DNA and RNA aptamers. Oligonucleotides. 2009;19(3):209–222. doi: 10.1089/oli.2009.0199.
  19. Maier KE, Levy M. From selection hits to clinical leads: progress in aptamer discovery. Mol Ther Methods Clin Dev. 2016;5:16014. doi: 10.1038/mtm.2016.14.
  20. Bruno JG. A review of therapeutic aptamer conjugates with emphasis on new approaches. Pharmaceuticals (Basel). 2013;6(3):340–357. doi: 10.3390/ph6030340.
  21. Rohloff JC, Gelinas AD, Jarvis TC, et al. Nucleic acid ligands with protein-like side chains: modified aptamers and their use as diagnostic and therapeutic agents. Mol Ther Nucleic Acids. 2014;3(10):e201. doi: 10.1038/mtna.2014.49.
  22. Thiel K. Oligo oligarchy-the surprisingly small world of aptamers. Nat Biotechnol. 2004;22(6):649–651. doi: 10.1038/nbt0604-649.
  23. Lewis K. Platforms for antibiotic discovery. Nat Rev Drug Discov. 2013;12(5):371–387. doi: 10.1038/nrd3975.
  24. Ozalp VC, Bilecen K, Kavruk M, Oktem HA. Antimicrobial aptamers for detection and inhibition of microbial pathogen growth. Future Microbiol. 2013;8(3):387–401. doi: 10.2217/fmb.12.149.
  25. Shum KT, Lui EL, Wong SC, et al. Aptamer-mediated inhibition of Mycobacterium tuberculosis polyphosphate kinase 2. Biochemistry. 2011;50(15):3261–3271. doi: 10.1021/bi2001455.
  26. Baig IA, Moon JY, Lee SC, et al. Development of ssDNA aptamers as potent inhibitors of Mycobacterium tuberculosis acetohydroxyacid synthase. Biochim Biophys Acta. 2015;1854(10 Pt A):1338–1350. doi: 10.1016/j.bbapap.2015.05.003.
  27. Gokhale K, Tilak B. Mechanisms of bacterial acetohydroxyacid synthase (AHAS) and specific inhibitors of Mycobacterium tuberculosis AHAS as potential drug candidates against tuberculosis. Curr Drug Targets. 2015;16(7):689–699. doi: 10.2174/13894501166 66150416115547.
  28. Schlesinger SR, Lahousse MJ, Foster TO, Kim SK. Metallo-β- lactamases and aptamer-based inhibition. Pharmaceuticals (Basel). 2011;4(2):419–428. doi: 10.3390/ph4020419.
  29. Teng J, Yuan F, Ye Y, et al. Aptamer-based technologies in foodborne pathogen detection. Front Microbiol. 2016;7:1426. doi: 10.3389/fmicb.2016.01426.
  30. Hamula CL, Peng H, Wang Z, et al. The effects of SELEX conditions on the resultant aptamer pools in the selection of aptamers binding to bacterial cells. J Mol Evol. 2015;81(5–6):194–209. doi: 10.1007/s00239-015-9711-y.
  31. Kolovskaya OS, Savitskaya AG, Zamay TN, et al. Development of bacteriostatic DNA aptamers for salmonella. J Med Chem. 2013;56(4):1564–1572. doi: 10.1021/jm301856j.
  32. Ohuchi S. Cell-SELEX Technology. Biores Open Access. 2012;1(6):265–272. doi: 10.1089/biores.2012.0253.
  33. Chen F, Zhou J, Luo F, et al. Aptamer from whole-bacterium SELEX as new therapeutic reagent against virulent Mycobacterium tuberculosis. Biochem Biophys Res Commun. 2007;357(3):743–748. doi: 10.1016/j.bbrc.2007.04.007.
  34. Pan Q, Wang Q, Sun X, et al. Aptamer against mannose-capped lipoarabinomannan inhibits virulent Mycobacterium tuberculosis infection in mice and rhesus monkeys. Mol Ther. 2014;22(5):940– 951. doi: 10.1038/mt.2014.31.
  35. Galili U. Anti-Gal: an abundant human natural antibody of multiple pathogeneses and clinical benefits. Immunology. 2013;140(1):1–11. doi: 10.1111/imm.12110.
  36. Kristian SA, Hwang JH, Hall B, et al. Retargeting pre-existing human antibodies to a bacterial pathogen with an alpha-Gal conjugated aptamer. J Mol Med (Berl). 2015;93(6):619–631. doi: 10.1007/ s00109-015-1280-4.
  37. Abdel-Motal UM, Guay HM, Wigglesworth K, et al. Immunogenicity of influenza virus vaccine is increased by anti-gal-mediated targeting to antigen-presenting cells. J Virol. 2007;81(17):9131– 9141. doi: 10.1128/JVI.00647-07.
  38. Bruno JG, Carrillo MP, Phillips T. In vitro antibacterial effects of antilipopolysaccharide DNA aptamer-C1qrs complexes. Folia Microbiol (Praha). 2008;53(4):295–302. doi: 10.1007/s12223-008- 0046-6.
  39. Dixon TC, Fadl AA, Koehler TM, et al. Early Bacillus anthracis-macrophage interactions: intracellular survival survival and escape. Cell Microbiol. 2000;2(6):453–463. doi: 10.1046/j.1462- 5822.2000.00067.x.
  40. Ali SR, Timmer AM, Bilgrami S, et al. Anthrax toxin induces macrophage death by p38 MAPK inhibition but leads to inflammasome activation via ATP leakage. Immunity. 2011;35(1):34–44. doi: 10.1016/j.immuni.2011.04.015.
  41. Ribet D, Cossart P. How bacterial pathogens colonize their hosts and invade deeper tissues. Microbes Infect. 2015;17(3):173–183. doi: 10.1016/j.micinf.2015.01.004.
  42. Foster TJ, Geoghegan JA, Ganesh VK, Hook M. Adhesion, invasion and evasion: the many functions of the surface proteins of Staphylococcus aureus. Nat Rev Microbiol. 2014;12(1):49–62. doi: 10.1038/nrmicro3161.
  43. Pan Q, Zhang XL, Wu HY, et al. Aptamers that preferentially bind type IVB pili and inhibit human monocytic-cell invasion by Salmonella enterica serovar typhi. Antimicrob Agents Chemother. 2005;49(10):4052–4060. doi: 10.1128/aac.49.10.4052-4060.2005.
  44. Balcazar JL, Subirats J, Borrego CM. The role of biofilms as environmental reservoirs of antibiotic resistance. Front Microbiol. 2015;6:1216. doi: 10.3389/fmicb.2015.01216.
  45. Ning Y, Cheng L, Ling M, et al. Efficient suppression of biofilm formation by a nucleic acid aptamer. Pathog Dis. 2015;73(6):ftv034. doi: 10.1093/femspd/ftv034.
  46. Chen F, Zhang X, Zhou J, et al. Aptamer inhibits Mycobacterium tuberculosis (H37Rv) invasion of macrophage. Mol Biol Rep. 2012;39(3):2157–2162. doi: 10.1007/s11033-011-0963-3.
  47. Feng C, Dai S, Wang L. Optical aptasensors for quantitative detection of small biomolecules: a review. Biosens Bioelectron. 2014;59:64–74. doi: 10.1016/j.bios.2014.03.014.
  48. Hurwitz M, Eliot RS. Arrhythmias in acute myocardial infarction. Dis Chest. 1964;45(6):616–626. doi: 10.1378/chest.45.6.616.
  49. Bhardwaj AK, Vinothkumar K, Rajpara N. Bacterial quorum sensing inhibitors: attractive alternatives for control of infectious pathogens showing multiple drug resistance. Recent Pat Antiinfect Drug Discov. 2013;8(1):68–83. doi: 10.2174/1574891x11308010012.
  50. Zhao ZG, Yu YM, Xu BY, et al. Screening and anti-virulent study of N-acyl homoserine lactones DNA aptamers against Pseudomonas aeruginosa quorum sensing. Biotechnol Bioprocess Eng. 2013;18(2):406–412. doi: 10.1007/s12257-012-0556-6.
  51. Cai S, Singh BR. Strategies to design inhibitors of Clostridium botulinum neurotoxins. Infect Disord Drug Targets. 2007;7(1):47–57. doi: 10.2174/187152607780090667.
  52. Tok JB, Fischer NO. Single microbead SELEX for efficient ssDNA aptamer generation against botulinum neurotoxin. Chem Commun (Camb). 2008;(16):1883–1885. doi: 10.1039/b717936g.
  53. Chang TW, Blank M, Janardhanan P, et al. In vitro selection of RNA aptamers that inhibit the activity of type A botulinum neurotoxin. Biochem Biophys Res Commun. 2010;396(4):854–860. doi: 10.1016/j.bbrc.2010.05.006.
  54. Jacobsen JA, Jourden JLM, Mille MT, Cohen SM. To bind zinc or not to bind zinc: an examination of innovative approaches to improved metalloproteinase inhibition. Biochim Biophys Acta. 2010;1803(1):72–94. doi: 10.1016/j.bbamcr.2009.08.006.
  55. Kolesnikov AV, Kozyr’ AV, Shemyakin IG. The prospects for using aptamers in diagnosing bacterial infections. Mol. Gen. Mikrobiol. Virol. 2012;27(2):49–55. doi: 10.3103/ s0891416812020048
  56. Hong KL, Sooter LJ. Single-stranded DNA aptamers against pathogens and toxins: identification and biosensing applications. Biomed Res Int. 2015;2015:419318. doi: 10.1155/2015/419318.
  57. Bruno JG, Richarte AM, Carrillo MP, Edge A. An aptamer beacon responsive to botulinum toxins. Biosens Bioelectron. 2012;31(1):240–243. doi: 10.1016/j.bios.2011.10.024.
  58. Klussmann S, Nolte A, Bald R, et al. Mirror-image RNA that binds D-adenosine. Nat Biotechnol. 1996;14(9):1112–1115. doi: 10.1038/ nbt0996-1112.
  59. Purschke WG, Radtke F, Kleinjung F, Klussmann S. A DNA Spiegelmer to staphylococcal enterotoxin B. Nucleic Acids Res. 2003;31(12):3027–3032. doi: 10.1093/nar/gkg413.
  60. Vivekananda J, Salgado C, Millenbaugh NJ. DNA aptamers as a novel approach to neutralize Staphylococcus aureus alphatoxin. Biochem Biophys Res Commun. 2014;444(3):433–438. doi: 10.1016/j.bbrc.2014.01.076.
  61. Wang K, Gan L, Jiang L, et al. Neutralization of staphylococcal enterotoxin B by an aptamer antagonist. Antimicrob Agents Chemother. 2015;59(4):2072–2077. doi: 10.1128/AAC.04414-14.
  62. Berens C, Groher F, Suess B. RNA aptamers as genetic control devices: the potential of riboswitches as synthetic elements for regulating gene expression. Biotechnol J. 2015;10(2):246–257. doi: 10.1002/biot.201300498.
  63. Winkler W, Nahvi A, Breaker RR. Thiamine derivatives bind messenger RNAs directly to regulate bacterial gene expression. Nature. 2002;419(6910):952–956. doi: 10.1038/nature01145.
  64. Cressina E, Chen L, Moulin M, et al. Identification of novel ligands for thiamine pyrophosphate (TPP) riboswitches. Biochem Soc Trans. 2011;39(2):652–657. doi: 10.1042/BST0390652.
  65. Mandal M, Breaker RR. Gene regulation by riboswitches. Nat Rev Mol Cell Biol. 2004;5(6):451–463. doi: 10.1038/nrm1403.
  66. Wittmann A, Suess B. Engineered riboswitches: Expanding researchers’ toolbox with synthetic RNA regulators. FEBS Lett. 2012;586(15):2076–2083. doi: 10.1016/j.febslet.2012.02.038.
  67. Topp S, Gallivan JP. Emerging applications of riboswitches in chemical biology. ACS Chem Biol. 2010;5(1):139–148. doi: 10.1021/ cb900278x.
  68. Trausch JJ, Batey RT. Design of modular “plug-and-play” expression platforms derived from natural riboswitches for engineering novel genetically encodable RNA regulatory devices. Methods Enzymol. 2015;550:41–71. doi: 10.1016/bs.mie.2014.10.031.
  69. Hughes D, Karlen A. Discovery and preclinical development of new antibiotics. Ups J Med Sci. 2014;119(2):162–169. doi: 10.3109/03009734.2014.896437.
  70. Ling LL, Schneider T, Peoples AJ, et al. A new antibiotic kills pathogens without detectable resistance. Nature. 2015;517(7535):455– 459. doi: 10.1038/nature14098.
  71. Andries K, Verhasselt P, Guillemont J, et al. A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. Science. 2005;307(5707):223–227. doi: 10.1126/science.1106753.
  72. Kavruk M, Celikbicak O, Ozalp VC, et al. Antibiotic loaded nanocapsules functionalized with aptamer gates for targeted destruction of pathogens. Chem Commun (Camb). 2015;51(40):8492–8495. doi: 10.1039/c5cc01869b.
  73. Song MY, Jurng J, Park YK, Kim BC. An aptamer cocktailfunctionalized photocatalyst with enhanced antibacterial efficiency towards target bacteria. J Hazard Mater. 2016;318:247–254. doi: 10.1016/j.jhazmat.2016.07.016.
  74. Ornellas PO, Antunes LD, Fontes KB, et al. Effect of the antimicrobial photodynamic therapy on microorganism reduction in deep caries lesions: a systematic review and meta-analysis. J Biomed Opt. 2016;21(9):90901. doi: 10.1117/1.jbo.21.9.090901.
  75. Zoccolillo ML, Rogers SC, Mang TS. Antimicrobial photodynamic therapy of S. mutans biofilms attached to relevant dental materials. Lasers Surg Med. Forthcoming 2016. doi: 10.1002/lsm.22534.
  76. Meitert J, Aram R, Wiesemann K, et al. Monitoring the expression level of coding and non-coding RNAs using a TetR inducing aptamer tag. Bioorg Med Chem. 2013;21(20):6233–6238. doi: 10.1016/j.bmc.2013.07.035.
  77. Chaloin L, Lehmann MJ, Sczakiel G, Restle T. Endogenous expression of a high-affinity pseudoknot RNA aptamer suppresses replication of HIV-1. Nucleic Acids Res. 2002;30(18):4001–4008. doi: 10.1093/nar/gkf522.
  78. Yosef I, Manor M, Kiro R, Qimron U. Temperate and lytic bacteriophages programmed to sensitize and kill antibiotic-resistant bacteria. Proc Natl Acad Sci U S A. 2015;112(23):7267–7272. doi: 10.1073/pnas.1500107112.
  79. Cotter PD, Ross RP, Hill C. Bacteriocins - a viable alternative to antibiotics? Nat Rev Microbiol. 2013;11(2):95–105. doi: 10.1038/ nrmicro2937.
  80. Lee CH, Han SR, Lee SW. Therapeutic applications of aptamerbased riboswitches. Nucleic Acid Ther. 2016;26(1):44–51. doi: 10.1089/nat.2015.0570.
  81. Vazquez-Anderson J, Contreras LM. Regulatory RNAs: charming gene management styles for synthetic biology applications. RNA Biol. 2013;10(12):1778–1797. doi: 10.4161/rna.27102.
  82. Wang S, Kong Q, Curtiss R. New technologies in developing recombinant attenuated Salmonella vaccine vectors. Microb Pathog. 2013;58:17–28. doi: 10.1016/j.micpath.2012.10.006.
  83. Mechaly A, Levy H, Epstein E, et al. A novel mechanism for antibody-based anthrax toxin neutralization: inhibition of preporeto-pore conversion. J Biol Chem. 2012;287(39):32665–32673. doi: 10.1074/jbc.M112.400473.
  84. Tian L, Heyduk T. Bivalent ligands with long nanometer-scale flexible linkers. Biochemistry. 2009;48(2):264–275. doi: 10.1021/bi801630b.
  85. Hasegawa H, Savory N, Abe K, Ikebukuro K. Methods for improving aptamer binding affinity. Molecules. 2016;21(4):421. doi: 10.3390/molecules21040421.
  86. Diafa S, Hollenstein M. Generation of aptamers with an expanded chemical repertoire. Molecules. 2015;20(9):16643–16671. doi: 10.3390/molecules200916643.
  87. Gupta S, Hirota M, Waugh SM, et al. Chemically modified DNA aptamers bind interleukin-6 with high affinity and inhibit signaling by blocking its interaction with interleukin-6 receptor. J Biol Chem. 2014;289(12):8706–8719. doi: 10.1074/jbc.M113.532580.
  88. Lollo B, Steele F, Gold L. Beyond antibodies: new affinity reagents to unlock the proteome. Proteomics. 2014;14(6):638–644. doi: 10.1002/pmic.201300187.

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