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Volume 167, Issue 1

Predatory bacteria as living antibiotics – where are we now? Open Access

Abstract

Antimicrobial resistance (AMR) is a global health and economic crisis. With too few antibiotics in development to meet current and anticipated needs, there is a critical need for new therapies to treat Gram-negative infections. One potential approach is the use of living predatory bacteria, such as (small Gram-negative bacteria that naturally invade and kill Gram-negative pathogens of humans, animals and plants). Moving toward the use of as a ‘living antibiotic’ demands the investigation and characterization of these bacterial predators in biologically relevant systems. We review the fundamental science supporting the feasibility of predatory bacteria as alternatives to antibiotics.

  • Received:
  • Accepted:
  • Published Online:
Keyword(s): Alternatives to antibiotics , AMR , Antimicrobial resistance , Bacteriophage , Living antibiotics and Predatory bacteria
Funding
This study was supported by the:
  • Wellcome Trust (Award 209437/Z/17/Z)
    • Principle Award Recipient: NotApplicable
© 2021 The Authors
  • This is an open-access article distributed under the terms of the Creative Commons Attribution License. This article was made open access via a Publish and Read agreement between the Microbiology Society and the corresponding author’s institution.
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2021-01-19
2023-03-22
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References

  1. WHO 2020; Antimicrobial resistance. https://www.who.int/health-topics/antimicrobial-resistance
  2. Livermore DM. Has the era of untreatable infections arrived?. J Antimicrob Chemother 2009; 64:i29–36
     [Google Scholar]
  3. CDC Antibiotic resistance threats in the United States. http://www.cdc.gov/DrugResistance/Biggest-Threats.html ; 2019
  4. O’Neill J. The review on antimicrobial resistance. tackling drug-resistant infections globally: final report and recommendations. https://amr-review.org/Publications.html ; 2016
  5. Morehead MS, Scarbrough C. Emergence of global antibiotic resistance. Prim Care 2018; 45:467–484
     [Google Scholar]
  6. Tacconelli E, Carrara E, Savoldi A, Harbarth S, Mendelson M et al. Discovery, research, and development of new antibiotics: the WHO priority list of antibiotic-resistant bacteria and tuberculosis. Lancet Infect Dis 2018; 18:318–327
     [Google Scholar]
  7. Laxminarayan R, Van Boeckel T, Frost I, Kariuki S, Khan EA et al. The Lancet infectious diseases Commission on antimicrobial resistance: 6 years later. Lancet Infect Dis 2020; 20:e51–e60
     [Google Scholar]
  8. The Pew Charitable Trusts A Scientific Roadmap for Antibiotic Discovery https://www.pewtrusts.org/en/research-and-analysis/reports/2016/05/a-scientific-roadmap-for-antibiotic-discovery ; 2016
  9. Luepke KH, Suda KJ, Boucher H, Russo RL, Bonney MW et al. Iii past, present, and future of antibacterial economics: increasing bacterial resistance, limited antibiotic pipeline, and societal implications. Pharmacotherapy 2017; 37:71–84
     [Google Scholar]
  10. Hesterkamp T. Antibiotics Clinical Development and Pipeline. How to Overcome the Antibiotic Crisis Current Topics in Microbiology and Immunology 398 Cham: Springer; 2015 pp 447–474
     [Google Scholar]
  11. Livermore DM. On behalf of the British Society for antimicrobial chemotherapy Working Party on the urgent need: regenerating antibacterial drug discovery and development B, Martin, Carrs O, Cassell G, fishman N, a Guidos R, et al. discovery research: the scientific challenge of finding new antibiotics. J Antimicrob Chemother 2011; 66:1941–1944
     [Google Scholar]
  12. Ardal C, Balasegaram M, Laxminarayan R, McAdams D, Outterson K et al. Antibiotic development - economic, regulatory and societal challenges. Nat Rev Microbiol. 2019
     [Google Scholar]
  13. Sharland MGS, Huttner B, Moja L, Pulcini C, Zeng M et al. Eml expert Committee and antibiotic Working Group. encouraging AWaRe-ness and discouraging inappropriate antibiotic use-the new 2019 essential medicines list becomes a global antibiotic stewardship tool. Lancet Infect Dis 2019; 19:1278–1280
     [Google Scholar]
  14. Lukacik P, Barnard TJ, Keller PW, Chaturvedi KS, Seddiki N et al. Structural engineering of a phage lysin that targets gram-negative pathogens. Proc Natl Acad Sci U S A 2012; 109:9857–9862
     [Google Scholar]
  15. Allen HK, Trachsel J, Looft T, Casey TA. Finding alternatives to antibiotics. In Bush K. editor Antimicrobial Therapeutics Reviews: Infectious Diseases of Current and Emerging Concern 13232014 Annals of the New York Academy of Sciences; pp 91–100
     [Google Scholar]
  16. Ghosh C, Sarkar P, Issa R, Haldar J. Alternatives to conventional antibiotics in the era of antimicrobial resistance. Trends in Microbiology 2019; 27:323–338
     [Google Scholar]
  17. Duke-Margolis Center for Health Policy Understanding development challenges associated emerging non-traditional-antibiotics. https://healthpolicy.duke.edu/events/understandingdevelopment-challenges-associated-emerging-non-traditional-antibiotics ; 2018
  18. Czaplewski L, Bax R, Clokie M, Dawson M, Fairhead H et al. Alternatives to antibiotics-a pipeline Portfolio review. Lancet Infect Dis 2016; 16:239–251
     [Google Scholar]
  19. Tse BN, Adalja AA, Houchens C, Larsen J, Inglesby TV et al. Challenges and opportunities of nontraditional approaches to treating bacterial infections. Cli Infect Dis 2017; 65:495–500
     [Google Scholar]
  20. Rello J, Parisella FR, Perez A. Alternatives to antibiotics in an era of difficult-to-treat resistance: new insights. Expert Rev Clin Pharmacol 2019; 12:635–642
     [Google Scholar]
  21. Theuretzbacher U, Piddock LJV. Non-traditional antibacterial therapeutic options and challenges. Cell Host Microbe 2019; 26:61–72
     [Google Scholar]
  22. Rex JH, Fernandez Lynch H, Cohen IG, Darrow JJ, Outterson K. Designing development programs for non-traditional antibacterial agents. Nat Commun 2019; 10:3416
     [Google Scholar]
  23. Theuretzbacher U, Outterson K, Engel A, Karlén A. The global preclinical antibacterial pipeline. Nat Rev Microbiol 2020; 18:275–285
     [Google Scholar]
  24. DARPA Pathogen predators program. https://www.darpa.mil/program/pathogenpredators ; 2015
  25. Pérez J, Moraleda-Muñoz A, Marcos-Torres FJ, Muñoz-Dorado J. Bacterial predation: 75 years and counting!. Environ Microbiol 2016; 18:766–779
     [Google Scholar]
  26. Negus D, Moore C, Baker M, Raghunathan D, Tyson J et al. Predator versus pathogen: how does predatory Bdellovibrio bacteriovorus interface with the challenges of killing gram-negative pathogens in a host setting?. Annu Rev Microbiol 2017; 71:441–457
     [Google Scholar]
  27. Laloux G. Shedding light on the cell biology of the predatory bacterium Bdellovibrio bacteriovorus . Front Microbiol 2020; 10:3136
     [Google Scholar]
  28. Sockett RE. Predatory lifestyle of Bdellovibrio bacteriovorus. Annu Rev Microbiol 2009; 63:523–539
     [Google Scholar]
  29. Milner DS, Ray LJ, Saxon EB, Lambert C, Till R et al. DivIVA controls progeny morphology and diverse para proteins regulate cell division or gliding motility in Bdellovibrio bacteriovorus. Front Microbiol 2020; 11:542
     [Google Scholar]
  30. Meek RW, Cadby IT, Moynihan PJ, Lovering AL. Structural basis for activation of a diguanylate cyclase required for bacterial predation in Bdellovibrio. Nat Commun. 2019; 10:4086
     [Google Scholar]
  31. Bratanis E, Andersson T, Lood R, Bukowska-Faniband E. Biotechnological potential of Bdellovibrio and like organisms and their secreted enzymes. Front Microbiol 2020; 11:662
     [Google Scholar]
  32. Harding CJ, Huwiler SG, Somers H, Lambert C, Ray LJ et al. A lysozyme with altered substrate specificity facilitates prey cell exit by the periplasmic predator Bdellovibrio bacteriovorus. Nat Commun 2020; 11:4817
     [Google Scholar]
  33. Caulton SG, Lovering AL. Bacterial invasion and killing by predatory Bdellovibrio primed by predator prey cell recognition and self protection. Curr Opin Microbiol 2020; 56:74–80
     [Google Scholar]
  34. Evans KJ, Lambert C, Sockett RE. Predation by Bdellovibrio bacteriovorus HD100 requires type IV pili. J Bacteriol Res 2007; 189:4850–4859
     [Google Scholar]
  35. Kuru E, Lambert C, Rittichier J, Till R, Ducret A et al. Fluorescent D-amino-acids reveal bi-cellular cell wall modifications important for Bdellovibrio bacteriovorus predation. Nat Microbiol 2017; 2:1648–1657
     [Google Scholar]
  36. Im H, Kim D, Ghim C-M, Mitchell RJ. Shedding light on microbial Predator–Prey population dynamics using a quantitative bioluminescence assay. Microbial Ecology 2014; 67:167–176
     [Google Scholar]
  37. Rendulic S, Jagtap P, Rosinus A, Eppinger M, Baar C et al. A predator unmasked: life cycle of Bdellovibrio bacteriovorus from a genomic perspective. Science 2004; 303:689–692
     [Google Scholar]
  38. Fenton AK, Kanna M, Woods RD, Aizawa SI, Sockett RE. Shadowing the actions of a predator: backlit fluorescent microscopy reveals synchronous nonbinary septation of predatory Bdellovibrio inside prey and exit through discrete bdelloplast pores. J Bacteriol 2010; 192:6329–6335
     [Google Scholar]
  39. Roschanski N, Klages S, Reinhardt R, Linscheid M, Strauch E. Identification of genes essential for prey-independent growth of Bdellovibrio bacteriovorus HD100. J Bacteriol 2011; 193:1745–1756
     [Google Scholar]
  40. Rittenberg SC, Shilo M. Early host damage in the infection cycle of Bdellovibrio bacteriovorus . J Bacteriol 1970; 102:149–160
     [Google Scholar]
  41. Lambert C, Ivanov P, Sockett RE. A transcriptional "Scream" early response of E. coli prey to predatory invasion by Bdellovibrio. Curr Microbiol 2010; 60:419–427
     [Google Scholar]
  42. Wolf AJ, Liu GY, Underhill DM. Inflammatory properties of antibiotic-treated bacteria. J Leukoc Biol 2017; 101:127–134
     [Google Scholar]
  43. Lambert C, Chang CY, Capeness MJ, Sockett RE. The first bite-profiling the predatosome in the bacterial pathogen Bdellovibrio. PLoS One 2010; 5:e8599
     [Google Scholar]
  44. Duncan MC, Gillette RK, Maglasang MA, Corn EA, Tai AK et al. High-Throughput analysis of gene function in the bacterial predator Bdellovibrio bacteriovorus. mBio 2019; 10:
     [Google Scholar]
  45. Schwudke D, Linscheid M, Strauch E, Appel B, Zahringer U et al. The obligate predatory Bdellovibrio bacteriovorus possesses a neutral lipid A containing alpha-D-Mannoses that replace phosphate residues: similarities and differences between the lipid as and the lipopolysaccharides of the wild type strain B. bacteriovorus HD100 and its host-independent derivative HI100. J Biol Chem 2003; 278:27502–27512
     [Google Scholar]
  46. Shanks RMQ, Davra VR, Romanowski EG, Brothers KM, Stella NA et al. An eye to a kill: using predatory bacteria to control gram-negative pathogens associated with ocular infections. PLoS ONE 2013; 8:e66723
     [Google Scholar]
  47. Monnappa AK, Bari W, Choi SY, Mitchell RJ. Investigating the responses of human epithelial cells to predatory bacteria. Scientific Reports 2016; 6:
     [Google Scholar]
  48. Gupta S, Tang C, Tran M, Kadouri DE. Effect of predatory bacteria on human cell lines. Plos One 2016; 11:
     [Google Scholar]
  49. Raghunathan D, Radford PM, Gell C, Negus D, Moore C et al. Engulfment, persistence and fate of Bdellovibrio bacteriovorus predators inside human phagocytic cells informs their future therapeutic potential. Scientific Reports 2019; 9:
     [Google Scholar]
  50. Rossol M, Heine H, Meusch U, Quandt D, Klein C et al. LPS-induced cytokine production in human monocytes and macrophages. Crit Rev Immunol 2011; 31:379–446
     [Google Scholar]
  51. Seidler RJ, Starr MP. Structure of the flagellum of Bdellovibrio bacteriovorus. J Bacteriol 1968; 95:1952–1955
     [Google Scholar]
  52. Findlay JS, Flick-Smith HC, Keyser E, Cooper IA, Williamson ED et al. Predatory bacteria can protect SKH-1 mice from a lethal plague challenge. Scientific Reports 2019; 9:
     [Google Scholar]
  53. Huh H, Wong S, St Jean J, Slavcev R. Bacteriophage interactions with mammalian tissue: therapeutic applications. Adv Drug Deliv Rev 2019; 145:4–17
     [Google Scholar]
  54. Moller-Olsen C, SFS H, Shukla RD, Feher T, Sagona AP. Engineered K1F bacteriophages kill intracellular Escherichia coli K1 in human epithelial cells. Sci Rep 2018; 8:17559
     [Google Scholar]
  55. Zhang L, Sun L, Wei R, Gao Q, He T et al. Intracellular Staphylococcus aureus control by virulent bacteriophages within MAC-T bovine mammary epithelial cells. Antimicrob Agents Chemother 2017; 61:
     [Google Scholar]
  56. Westergaard JM, Kramer TT. Bdellovibrio and the intestinal flora of vertebrates. Appl Environ Microbiol 1977; 34:506–511
     [Google Scholar]
  57. Atterbury RJ, Hobley L, Till R, Lambert C, Capeness MJ et al. Effects of orally administered Bdellovibrio bacteriovorus on the well-being and Salmonella colonization of young chicks. Appl Environ Microbiol 2011; 77:5794–5803
     [Google Scholar]
  58. Romanowski EG, Stella NA, Brothers KM, Yates KA, Funderburgh ML et al. Predatory bacteria are nontoxic to the rabbit ocular surface. Scientific Reports 2016; 6:
     [Google Scholar]
  59. Shatzkes K, Singleton E, Tang C, Zuena M, Shukla S et al. Predatory bacteria attenuate Klebsiella pneumoniae burden in rat lungs. mBio 2016; 7:
     [Google Scholar]
  60. Shatzkes K, Singleton E, Tang C, Zuena M, Shukla S et al. Examining the efficacy of intravenous administration of predatory bacteria in rats. Scientific Reports 2017; 7:
     [Google Scholar]
  61. Shatzkes K, Tang C, Singleton E, Shukla S, Zuena M et al. Effect of predatory bacteria on the gut bacterial microbiota in rats. Scientific Reports 2017; 7:
     [Google Scholar]
  62. Shatzkes K, Chae R, Tang C, Ramirez GC, Mukherjee S et al. Examining the safety of respiratory and intravenous inoculation of Bdellovibrio bacteriovorus and Micavibrio aeruginosavorus in a mouse model. Scientific Reports 2015; 5:
     [Google Scholar]
  63. Willis AR, Moore C, Mazon-Moya M, Krokowski S, Lambert C et al. Injections of predatory bacteria work alongside host immune cells to treat Shigella infection in zebrafish larvae. Curr Biol 2016; 26:3343–3351
     [Google Scholar]
  64. Dashiff A, Junka RA, Libera M, Kadouri DE. Predation of human pathogens by the predatory bacteria Micavibrio aeruginosavorus and Bdellovibrio bacteriovorus. J Appl Microbiol 2011; 110:431–444
     [Google Scholar]
  65. Kadouri DE, To K, Shanks RMQ, Doi Y. Predatory bacteria: a potential ally against multidrug-resistant gram-negative pathogens. PLoS ONE 2013; 8:e63397
     [Google Scholar]
  66. Patini R, Cattani P, Marchetti S, Isola G, Quaranta G et al. Evaluation of predation capability of Periodontopathogens bacteria by Bdellovibrio bacteriovorus HD100. An in vitro study. Materials 2019; 12:E2008
     [Google Scholar]
  67. Russo R, Chae R, Mukherjee S, Singleton EJ, Occi JL et al. Susceptibility of select agents to predation by predatory bacteria. Microorganisms 2015; 3:903–912
     [Google Scholar]
  68. Baker M, Negus D, Raghunathan D, Radford P, Moore C et al. Measuring and modelling the response of Klebsiella pneumoniae KPC prey to Bdellovibrio bacteriovorus predation, in human serum and defined buffer. Scientific Reports 2017; 7:
     [Google Scholar]
  69. Dashiff A, Kadouri DE. Predation of oral pathogens by Bdellovibrio bacteriovorus 109J. Mol Oral Microbiol 2011; 26:19–34
     [Google Scholar]
  70. Sun Y, JZ Y, Hou YB, Chen HL, Cao JM et al. Predation efficacy of Bdellovibrio bacteriovorus on multidrug-resistant clinical pathogens and their corresponding biofilms. Jpn J Infect Dis 2017; 70:485–489
     [Google Scholar]
  71. Kadouri D, O'Toole GA. Susceptibility of biofilms to Bdellovibrio bacteriovorus attack. Appl Environ Microbiol 2005; 71:4044–4051
     [Google Scholar]
  72. Gilbert P, Maira-Litran T, McBain AJ, Rickard AH, Whyte FW. The physiology and collective recalcitrance of microbial biofilm communities. Adv Microb Physiol 2002; 46:202–256
     [Google Scholar]
  73. Im H, Choi SY, Son S, Mitchell RJ. Combined application of bacterial predation and violacein to kill polymicrobial pathogenic communities. Scientific Reports 2017; 7:14415
     [Google Scholar]
  74. Im H, Son S, Mitchell RJ, Ghim C-M. Serum albumin and osmolality inhibit Bdellovibrio bacteriovorus predation in human serum. Scientific Reports 2017; 7:5896
     [Google Scholar]
  75. Dharani S, Kim DH, Shanks RMQ, Doi Y, Kadouri DE. Susceptibility of colistin-resistant pathogens to predatory bacteria. Res Microbiol 2018; 169:52–55
     [Google Scholar]
  76. Bengoechea JA, Sa Pessoa J. Klebsiella pneumoniae infection biology: living to counteract host defences. FEMS Microbiology Review 2019; 43:123–144
     [Google Scholar]
  77. Helaine S, Cheverton AM, Watson KG, Faure LM, Matthews SA et al. Internalization of Salmonella by macrophages induces formation of nonreplicating persisters. Science 2014; 343:204–208
     [Google Scholar]
  78. Donnenberg MS. Pathogenic strategies of enteric bacteria. Nature 2000; 406:768–774
     [Google Scholar]
  79. Torraca V, Mostowy S. Zebrafish infection: from pathogenesis to cell biology. Trends Cell Biol 2018; 28:143–156
     [Google Scholar]
  80. Gomes MC, Mostowy S. The case for modeling human infection in zebrafish. Trends Microbiol 2020; 28:10–18
     [Google Scholar]
  81. Howe K, Clark MD, Torroja CF, Torrance J, Berthelot C et al. The zebrafish reference genome sequence and its relationship to the human genome. Nature 2013; 496:498–503
     [Google Scholar]
  82. Meijer AH, Spaink HP. Host-Pathogen interactions made transparent with the zebrafish model. Curr Drug Targets 2011; 12:1000–1017
     [Google Scholar]
  83. Russo R, Kolesnikova I, Kim T, Gupta S, Pericleous A et al. Susceptibility of virulent Yersinia pestis bacteria to predator bacteria in the lungs of mice. Microorganisms 2019; 7:
     [Google Scholar]
  84. Findlay JS, Flick-Smith HC, Keyser E, Cooper IA, Williamson ED et al. Predatory bacteria can protect SKH-1 mice from a lethal plague challenge. Sci Rep 2019; 9:7225
     [Google Scholar]
  85. Boileau MJ, Clinkenbeard KD, Iandolo JJ. Assessment of Bdellovibrio bacteriovorus 109J killing of Moraxella bovis in an in vitro model of infectious bovine keratoconjunctivitis. Can J Vet Res 2011; 75:285–291
     [Google Scholar]
  86. Boileau MJ, Mani R, Breshears MA, Gilmour M, Taylor JD et al. Efficacy of Bdellovibrio bacteriovorus 109J for the treatment of dairy calves with experimentally induced infectious bovine keratoconjunctivitis. Am J Vet Res 2016; 77:1017–1028
     [Google Scholar]
  87. Kutateladze M, Adamia R. Bacteriophages as potential new therapeutics to replace or supplement antibiotics. Trends Biotechnol 2010; 28:591–595
     [Google Scholar]
  88. Aslam S, Schooley RT. What’s old is new again: bacteriophage therapy in the 21st century. Antimicrob Agents Chemother 2019; 64:
     [Google Scholar]
  89. Schooley RT, Biswas B, Gill JJ, Hernandez-Morales A, Lancaster J et al. Development and use of personalized bacteriophage-based therapeutic cocktails to treat a patient with a disseminated resistant Acinetobacter baumannii infection. Antimicrobial Agents and Chemotherapy 2017; 61:
     [Google Scholar]
  90. Dedrick RM, Guerrero-Bustamante CA, Garlena RA, Russell DA, Ford K et al. Engineered bacteriophages for treatment of a patient with a disseminated drug-resistant Mycobacterium abscessus. Nat Med 2019; 25:730–733
     [Google Scholar]
  91. Alexander M. Why microbial predators and parasites do not eliminate their prey and hosts. Annu Rev Microbiol 1981; 35:113–133
     [Google Scholar]
  92. van den Ende P. Predator-prey interactions in continuous culture. Science 1973; 181:562–564
     [Google Scholar]
  93. Varon M. Selection of predation-resistant bacteria in continuous culture. Nature 1979; 277:386–388
     [Google Scholar]
  94. Bhandare S, Colom J, Baig A, Ritchie JM, Bukhari H et al. Reviving phage therapy for the treatment of cholera. J Infect Dis 2019; 219:786–794
     [Google Scholar]
  95. Hobley L, Summers JK, Till R, Milner DS, Atterbury RJ et al. Dual predation by bacteriophage and Bdellovibrio bacteriovorus can eradicate Escherichia coli prey in situations where single predation cannot. J Bacteriol 2020; 202:
     [Google Scholar]
  96. Merril CR, Biswas B, Carlton R, Jensen NC, Creed GJ et al. Long-circulating bacteriophage as antibacterial agents. Proc Natl Acad Sci U S A 1996; 93:3188–3192
     [Google Scholar]
  97. Garcia R, Latz S, Romero J, Higuera G, Garcia K et al. Bacteriophage production models: an overview. Front Microbiol 2019; 10:1187
     [Google Scholar]
  98. Boileau MJ, Mani R, Clinkenbeard KD. Lyophilization of Bdellovibrio bacteriovorus 109J for long-term storage. Curr Protoc Microbiol 2017; 45:7B 3 1-7B 3 15
     [Google Scholar]
  99. Robson MC, Mannari RJ, Smith PD, Payne WG. Maintenance of wound bacterial balance. Am J Surg 1999; 178:399–402
     [Google Scholar]
  100. Robson MC. Wound infection. A failure of wound healing caused by an imbalance of bacteria. Surg Clin North Am 1997; 77:637–650
     [Google Scholar]
  101. Greenwood DJ, Dos Santos MS, Huang S, Russell MRG, Collinson LM et al. Subcellular antibiotic visualization reveals a dynamic drug reservoir in infected macrophages. Science 2019; 364:1279–1282 [View Article]
     [Google Scholar]
  102. Rex JH, Outterson K. Antibiotic reimbursement in a model delinked from sales: a benchmark-based worldwide approach. Lancet Infect Dis 2016; 16:500–505 [View Article]
     [Google Scholar]
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