Exploring potential of vaginal Lactobacillus isolates from South African women for enhancing treatment for bacterial vaginosis

Autoři: Anna-Ursula Happel aff001;  Brian Kullin aff001;  Hoyam Gamieldien aff001;  Nicole Wentzel aff001;  Chambrez Z. Zauchenberger aff001;  Heather B. Jaspan aff001;  Smritee Dabee aff001;  Shaun L. Barnabas aff001;  Shameem Z. Jaumdally aff001;  Janan Dietrich aff004;  Glenda Gray aff004;  Linda-Gail Bekker aff001;  Remy Froissart aff007;  Jo-Ann S. Passmore aff001
Působiště autorů: Department of Pathology, Institute of Infectious Disease and Molecular Medicine (IDM), University of Cape Town, Cape Town, South Africa aff001;  Seattle Children’s Hospital, Seattle, United States of America aff002;  Family Centre for Research with Ubuntu (FAMCRU), Stellenbosch University, Tygerberg, South Africa aff003;  Perinatal HIV Research Unit (PHRU), Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa aff004;  Health Systems Research Unit, South African Medical Research Council, Cape Town, South Africa aff005;  Desmond Tutu HIV Foundation, University of Cape Town, Cape Town, South Africa aff006;  UMR MIVEGEC CNRS-IRD-UM, University Montpellier, Montpellier, France aff007;  NRF-DST CAPRISA Centre of Excellence in HIV Prevention, Cape Town, South Africa aff008;  National Health Laboratory Service (NHLS), Cape Town, South Africa aff009
Vyšlo v časopise: Exploring potential of vaginal Lactobacillus isolates from South African women for enhancing treatment for bacterial vaginosis. PLoS Pathog 16(6): e1008559. doi:10.1371/journal.ppat.1008559
Kategorie: Research Article
doi: 10.1371/journal.ppat.1008559


Antibiotics continue to be the standard-of-care for bacterial vaginosis (BV), although recurrence rates are high. Vaginal probiotics may improve durability of BV treatment, although few probiotics for vaginal health contain Lactobacillus spp. that commonly colonize the lower female genital tract. Characteristics of vaginal Lactobacillus strains from South African women were evaluated for their probiotic potential in vitro compared to strains from commercial vaginal products, including growth at varying pHs, ability to lower pH, produce D-/L-lactate and H2O2, influence growth of BV-associated Gardnerella vaginalis and Prevotella bivia, adherence to cervical cells and susceptibility to antibiotics. Fifty-seven Lactobacillus strains were purified from cervico-vaginal fluid, including L. crispatus, L. jensenii, L. gasseri, L. mucosae, and L. vaginalis. L crispatus strains grew better at pHs below 4.5 and lowered pH more effectively than other strains. Production of D-/L-lactate and H2O2 varied between Lactobacillus species and strains. Lactobacillus strains generally inhibited P. bivia more uniformly than G. vaginalis isolates. All vaginal Lactobacillus isolates were resistant to metronidazole while susceptibility to clindamycin varied. Furthermore, vaginal Lactobacillus strains tended to be broadly susceptible to penicillin, amoxicillin, rifampicin and rifabutin. Whole-genome-sequencing of five of the best-performing vaginal Lactobacillus strains confirmed their likely safety, due to antimicrobial resistance elements being largely absent, while putative intact prophages were present in the genomes of two of the five strains. Overall, vaginal Lactobacillus strains largely performed better in these in vitro assays than probiotic strains currently used in probiotics for vaginal health. Including the best-performing vaginal Lactobacillus isolates in a region-specific probiotic for vaginal health may result in improved BV treatment options.

Klíčová slova:

African people – Antibiotics – Bacterial vaginosis – Clindamycin – Cytokines – Lactobacillus – Microbiome – Probiotics


1. McKinnon LR, Achilles SL, Bradshaw CS, Burgener A, Crucitti T, Fredricks DN, et al. The Evolving Facets of Bacterial Vaginosis: Implications for HIV Transmission. AIDS Res Hum Retroviruses. 2019;35: 219–228. doi: 10.1089/AID.2018.0304 30638028

2. Boskey ER, Telsch KM, Whaley KJ, Moench TR, Cone RA. Acid production by vaginal flora in vitro is consistent with the rate and extent of vaginal acidification. Infect Immun. 1999;67: 5170–5175. 10496892

3. Aroutcheva A, Gariti D, Simon M, Shott S, Faro J, Simoes JA, et al. Defense factors of vaginal lactobacilli. Am J Obstet Gynecol. 2001;185: 375–379. doi: 10.1067/mob.2001.115867 11518895

4. Ravel J, Gajer P, Abdo Z, Schneider GM, Koenig SSK, McCulle SL, et al. Vaginal microbiome of reproductive-age women. Proc Natl Acad Sci. 2011;108: 4680–4687. doi: 10.1073/pnas.1002611107 20534435

5. Gajer P, Brotman RM, Bai G, Sakamoto J, Schütte UME, Zhong X, et al. Temporal dynamics of the human vaginal microbiota. Sci Transl Med. 2012;4: 132ra52. doi: 10.1126/scitranslmed.3003605 22553250

6. Clark P, Kurtzer T, Duff P. Role of Bacterial Vaginosis in Peripartum Infections. Infect Dis Obstet Gynecol. 1994;2: 179–183. doi: 10.1155/S106474499400061X 18475388

7. Nelson DB, Hanlon A, Nachamkin I, Haggerty C, Mastrogiannis DS, Liu C, et al. Early pregnancy changes in bacterial vaginosis-associated bacteria and preterm delivery. Paediatr Perinat Epidemiol. 2014;28: 88–96. doi: 10.1111/ppe.12106 24405280

8. Haggerty CL, Totten PA, Tang G, Astete SG, Ferris MJ, Norori J, et al. Identification of novel microbes associated with pelvic inflammatory disease and infertility. Sex Transm Infect. 2016; sextrans-2015-052285. doi: 10.1136/sextrans-2015-052285 26825087

9. Van de Wijgert JHHM, Morrison CS, Cornelisse PGA, Munjoma M, Moncada J, Awio P, et al. Bacterial vaginosis and vaginal yeast, but not vaginal cleansing, increase HIV-1 acquisition in African women. J Acquir Immune Defic Syndr. 2008;48: 203–210. doi: 10.1097/QAI.0b013e3181743936 18520679

10. Cohen CR, Lingappa JR, Baeten JM, Ngayo MO, Spiegel CA, Hong T, et al. Bacterial vaginosis associated with increased risk of female-to-male HIV-1 transmission: A prospective cohort analysis among african couples. PLoS Med. 2012;9: 18. doi: 10.1371/journal.pmed.1001251 22745608

11. Anahtar MN, Byrne EH, Doherty KE, Bowman BA, Yamamoto S, Soumillon M, et al. Inflammatory Responses in the Female Genital Tract. Immunity. 2016;42: 965–976. doi: 10.1016/j.immuni.2015.04.019.Cervicovaginal

12. Centers for Disease Control and Prevention. Sexually Transmitted Diseases Treatment Guidelines. In: Sexually Transmitted Diseases Treatment Guidelines. 2015.

13. Barrons R, Tassone D. Use of Lactobacillus probiotics for bacterial genitourinary infections in women: A review. Clin Ther. 2008;30: 453–468. doi: 10.1016/j.clinthera.2008.03.013 18405785

14. Vicariotto F, Mogna L, Del Piano M. Effectiveness of the Two Microorganisms Lactobacillus Formulated in Slow-release Vaginal Tablets, in Women Affected by Bacterial Vaginosis. J Clin Gastroenterol. 2014;48: S106–S112. doi: 10.1097/MCG.0000000000000226 25291116

15. Marcone V, Rocca G, Lichtner M, Calzolari E. Long-term vaginal administration of Lactobacillus rhamnosus as a complementary approach to management of bacterial vaginosis. Int J Gynecol Obstet. 2010;110: 223–226. doi: 10.1016/j.ijgo.2010.04.025 20573348

16. Martinez RCR, Franceschini A, Patta MC, Quintana SM, Gomes BC, De Martinis ECP, et al. Improved cure of bacterial vaginosis with single dose of tinidazole (2 g), Lactobacillus rhamnosus GR-1, and Lactobacillus reuteri RC-14: a randomized, double-blind, placebo-controlled trial. Can J Microbiol. 2009;55: 133–138. doi: 10.1139/w08-102 19295645

17. Reid G, Charbonneau D, Erb J, Kochanowski B, Beuerman D, Poehner R, et al. Oral use of Lactobacillus rhamnosus GR-1 and L. fermentum RC-14 significantly alters vaginal flora: Randomized, placebo-controlled trial in 64 healthy women. FEMS Immunol Med Microbiol. 2003;35: 131–134. doi: 10.1016/S0928-8244(02)00465-0 12628548

18. Happel A-U, Jaumdally SZ, Pidwell T, Cornelius T, Jaspan HB, Froissart R, et al. Probiotics for vaginal health in South Africa: what is on retailers ‘ shelves? BMC Womens Health. 2017;17. doi: 10.1186/s12905-017-0362-6 28103868

19. Mendes-soares H, Suzuki H, Hickey RJ, Forney LJ. Comparative Functional Genomics of Lactobacillus spp. Reveals Possible Mechanisms for Specialization of Vaginal Lactobacilli to Their Environment. J Bacteriol. 2014;196: 1458–1470. doi: 10.1128/JB.01439-13 24488312

20. Tomás J, Zonenschain D, Morelli L, Nader-Macías ME. Characterisation of potentially probiotic vaginal lactobacilli isolated from Argentinean women Characterisation of potentially probiotic vaginal lactobacilli isolated from Argentinean women. Br J Biomed Sci. 2005;62: 170–174. doi: 10.1080/09674845.2005.11732706 16411376

21. Atassi F, Brassart D, Grob P, Graf F, Servin AL. Lactobacillus strains isolated from the vaginal microbiota of healthy women inhibit Prevotella bivia and Gardnerella vaginalis in coculture and cell culture. Fem. 2006;48: 424–432. doi: 10.1111/j.1574-695X.2006.00162.x 17059467

22. Coudeyras S, Jugie G, Vermerie M, Forestier C. Adhesion of Human Probiotic Lactobacillus rhamnosus to Cervical and Vaginal Cells and Interaction with Vaginosis-Associated Pathogens. Infect Dis Obstet Gynecol. 2008. doi: 10.1155/2008/549640 19190778

23. Teixeira GS, Carvalho FP, Arantes RME, Nunes AC, Moreira JLS, Mendonc M, et al. Characteristics of Lactobacillus and Gardnerella vaginalis from women with or without bacterial vaginosis and their relationships in gnotobiotic mice. J Med Microbiol. 2012;61: 1074–1081. doi: 10.1099/jmm.0.041962-0 22539000

24. Castro J, Alves P, Sousa C, Cereija T, França Â, Jefferson KK, et al. Using an in-vitro biofilm model to assess the virulence potential of Bacterial Vaginosis or non- Bacterial Vaginosis Gardnerella vaginalis isolates. Sci Rep. 2015;5. doi: 10.1038/srep11640 26113465

25. Andreeva P, Shterev A, Danova S. Antimicrobial activity of vaginal lactobacilli against Gardnerella vaginalis and pathogens. Int J Adv Res Biol Sci. 2016;3: 200–207.

26. Huang Y, Adams MC. In vitro assessment of the upper gastrointestinal tolerance of potential probiotic dairy propionibacteria. Int J Food Microbiol. 2004;91: 253–260. doi: 10.1016/j.ijfoodmicro.2003.07.001 14984773

27. Silva J, Carvalho AS, Ferreira R, Vitorino R, Amado F, Domingues P, et al. Effect of the pH of growth on the survival of Lactobacillus delbrueckii subsp. bulgaricus to stress conditions during spray-drying. J Appl Microbiol. 2005;98: 775–782. doi: 10.1111/j.1365-2672.2004.02516.x 15715882

28. Hossein Nezhad M, Stenzel D, Britz M. Effect of growth at low pH on the cell surface properties of a typical strain of Lactobacillus casei group. Iran J Microbiol. 2010;2: 147–154. 22347564

29. Nardini P, Alberto R, Palomino Ñ, Parolin C, Laghi L, Foschi C, et al. Lactobacillus crispatus inhibits the infectivity of Chlamydia trachomatis elementary bodies, in vitro study. Sci Rep. 2016;6. doi: 10.1038/srep29024 27354249

30. O’Hanlon DEO, Moench TR, Cone RA. In vaginal fluid, bacteria associated with bacterial vaginosis can be suppressed with lactic acid but not hydrogen peroxide. BMC Infect Dis. 2011;11. doi: 10.1186/1471-2334-11-200 21771337

31. Aldunate M, Tyssen D, Johnson A, Zakir T, Sonza S, Moench T, et al. Vaginal concentrations of lactic acid potently inactivate HIV. J Antimicrob Chemother. 2013;68: 2015–2025. doi: 10.1093/jac/dkt156 23657804

32. Valore E V, Park CH, Igreti SL, Ganz T. Antimicrobial components of vaginal fluid. Am J Obs Gynecol. 2002;187: 561–568. doi: 10.1067/mob.2002.125280 12237628

33. Van Reenen CA, Dicks LMT. Horizontal gene transfer amongst probiotic lactic acid bacteria and other intestinal microbiota: what are the possibilities? A review. Arch Microbiol. 2011;193: 157–168. doi: 10.1007/s00203-010-0668-3 21193902

34. Stecher B, Denzler R, Maier L, Bernet F, Sanders MJ, Pickard DJ, et al. Gut inflammation can boost horizontal gene transfer between pathogenic and commensal Enterobacteriaceae. PNAS. 2012;109: 1269–1274. doi: 10.1073/pnas.1113246109 22232693

35. Gueimonde M, Sánchez B, Reyes-Gavilán CGDL, Margolles A. Antibiotic resistance in probiotic bacteria. Front Microbiol. 2013;4. doi: 10.3389/fmicb.2013.00202 23882264

36. Lennard K, Dabee S, Barnabas SL, Havyarimana E, Blakney A, Jaumdally SZ, et al. Microbial composition predicts genital inflammation and persistent bacterial vaginosis in adolescent South African women. Infect Immun. 2017;86: e00410–17. doi: 10.1128/IAI.00410-17 29038128

37. Boris S, Barbés C. Role played by lactobacilli in controlling the population of vaginal pathogens. Microbes Infect. 2000;2: 543–546. doi: 10.1016/s1286-4579(00)00313-0 10865199

38. Boskey ER, Cone RA, Whaley KJ, Moench TR. Origins of vaginal acidity: high D/L lactate ratio is consistent with bacteria being the primary source. Hum Reprod. 2001;16: 1809–1813. doi: 10.1093/humrep/16.9.1809 11527880

39. Hillier SL, Krohn MA, Rabe LK, Klebanoff SJ, Eschenbach DA. The normal vaginal flora, H2 O2-producing lac- tobacilli, and bacterial vaginosis in pregnant women. Clin Infect Dis. 1993;16: S273–281. doi: 10.1093/clinids/16.supplement_4.s273 8324131

40. Hawes SE, Hillier SL, Benedetti J, Stevens CE, Koutsky LA, Wolner-Hanssen P, et al. Hydrogen peroxide-produc- ing lactobacilli and acquisition of vaginal infections. J Infect Dis. 1996;174: 1058–63. doi: 10.1093/infdis/174.5.1058 8896509

41. Nahid P, Dorman SE, Alipanah N, Barry PM, Brozek JL, Cattamanchi A, et al. Official American Thoracic Society / Centers for Disease Control and Prevention / Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis. Clin Infect Dis. 2016;63: 853–867. doi: 10.1093/cid/ciw566 27621353

42. Hoover WW, Gerlach EH, Hoban DJ, Eliopoulos GM, Pfaller MA, Jones RN. Antimicrobial activity and spectrum of rifaximin, a new topical rifamycin derivative. Diagn Microbiol Infect Dis. 1993;16: 111–118. doi: 10.1016/0732-8893(93)90004-q 8385592

43. Kharsany AB, Hoosen AA, Van den Ende J. Antimicrobial susceptibilities of Gardnerella vaginalis. Antimicrob Agents Chemother. 1993;37: 2733 LP– 2735. doi: 10.1128/aac.37.12.2733 8109944

44. Fichorova RN, Yamamoto HS, Delaney ML, Onderdonk AB, Doncel GF. Novel Vaginal Microflora Colonization Model Providing New Insight into Microbicide Mechanism of Action. MBio. 2011;2: 1–10. doi: 10.1128/mBio.00168-11.Editor

45. Tomalka J, Ghneim K, Bhattacharyya S, Aid M, Barouch DH, Sekaly RP, et al. The sooner the better: innate immunity as a path toward the HIV cure. Curr Opin Virol. 2016;19: 85–91. doi: 10.1016/j.coviro.2016.07.003 27497036

46. Petrova MI, Reid G, Vaneechoutte M, Lebeer S. Lactobacillus iners: Friend or Foe? Trends Microbiol. 2017;25: 182–191. doi: 10.1016/j.tim.2016.11.007 27914761

47. Anahtar MN, Byrne EH, Fichorova RN, Kwon DS, Anahtar MN, Byrne EH, et al. Cervicovaginal Bacteria Are a Major Modulator of Host Inflammatory Responses in the Female Genital Article Cervicovaginal Bacteria Are a Major Modulator of Host Inflammatory Responses in the Female Genital Tract. Immunity. 2015;42: 965–976. doi: 10.1016/j.immuni.2015.04.019 25992865

48. Witkin SS, Mendes-Soares H, Linhares IM, Jayaram A, Ledger WJ, Forney LJ. Influence of Vaginal Bacteria and D—and L -Lactic Acid Isomers on Vaginal Extracellular Matrix Metalloproteinase Inducer: Implications for Protection against Upper Genital Tract Infections. MBio. 2013;4: e00460–13. doi: 10.1128/mBio.00460-13 23919998

49. Hutt P, Lapp E, Stsepetiva J, Smidt I, Taelma H, Borovkova N, et al. Characterisation of probiotic properties in human vaginal lactobacilli strains. Microb Ecol Health Dis. 2016;27.

50. Tachedjian G, Aldunate M, Bradshaw CS, Cone RA. The role of lactic acid production by probiotic Lactobacillus species in vaginal health. Res Microbiol. 2017;168: 782–792. doi: 10.1016/j.resmic.2017.04.001 28435139

51. Tachedjian G, Hanlon DEO, Ravel J. The implausible “in vivo” role of hydrogen peroxide as an antimicrobial factor produced by vaginal microbiota. Microbiome. 2018;6.

52. McLean NW, McGroarty JA. Growth Inhibition of Metronidazole-Susceptible and Metronidazole-Resistant Strains of Gardnerella vaginalis by Lactobacilli In Vitro. Appl Environ Microbiol. 1996;62: 1089–1092. 8975601

53. Patterson JL, Girerd PH, Karjane NW, Jefferson KK. Effect of biofilm phenotype on resistance of Gardnerella vaginalis to hydrogen peroxide and lactic acid. Am J Obstet Gynecol. 2007;170: e1–e7. doi: 10.1016/j.ajog.2007.02.027 17689638

54. Neut C, Mahieux S, Dubreuil LJ. Antibiotic susceptibility of probiotic strains: Is it reasonable to combine probiotics with antibiotics? Med Mal Infect. 2017;47: 477–483. doi: 10.1016/j.medmal.2017.07.001 28797834

55. Simoes J a, Aroutcheva a a, Shott S, Faro S. Effect of metronidazole on the growth of vaginal lactobacilli in vitro. Infect Dis Obstet Gynecol. 2001;9: 41–45. doi: 10.1155/S1064744901000072 11368258

56. Charteris WP, Kelly HPM, Morelli L, Collins JK. Antibiotic Susceptibility of Potentially Probiotic Lactobacillus Species. J Food Prot. 1998;6: 1636–1643.

57. Delgado S, Flórez AB, Mayo B. Antibiotic Susceptibility of Lactobacillus and Bifidobacterium Species from the Human Gastrointestinal Tract. Curr Microbiol. 2005;50: 202–207. doi: 10.1007/s00284-004-4431-3 15902467

58. Ocaña VS, Silva C, Nader-Macías ME. Antibiotic Susceptibility of Potentially Probiotic Vaginal Lactobacilli. Infect Dis Obstet Gynecol. 2006. doi: 10.1155/IDOG/2006/18182 17485797

59. Sims JE, Smith DE. The IL-1 family: regulators of immunity. Nat Rev Immunol. 2010;10: 89. Available: doi: 10.1038/nri2691 20081871

60. Rollenhagen C, Asin SN. IL-8 Decreases HIV-1 Transcription in Peripheral Blood Lymphocytes and Ectocervical Tissue Explants. JAIDS J Acquir Immune Defic Syndr. 2010;54. Available: https://journals.lww.com/jaids/Fulltext/2010/08150/IL_8_Decreases_HIV_1_Transcription_in_Peripheral.3.aspx

61. Mlisana K, Naicker N, Werner L, Roberts L, Van Loggerenberg F, Baxter C, et al. Symptomatic vaginal discharge is a poor predictor of sexually transmitted infections and genital tract inflammation in high-risk women in South Africa. J Infect Dis. 2012;206: 6–14. doi: 10.1093/infdis/jis298 22517910

62. Masson L, Passmore JAS, Liebenberg LJ, Werner L, Baxter C, Arnold KB, et al. Genital Inflammation and the Risk of HIV Acquisition in Women. Clin Infect Dis. 2015;61: 260–269. doi: 10.1093/cid/civ298 25900168

63. van Hoek AHAM, Mevius D, Guerra B, Mullany P, Roberts AP, Aarts HJM. Acquired antibiotic resistance genes: an overview. Front Microbiol. 2011;2: 203. doi: 10.3389/fmicb.2011.00203 22046172

64. Pavlova SI, Tao L. Induction of vaginal Lactobacillus phages by the cigarette smoke chemical benzo[a]pyrene diol epoxide. Mutat Res. 2000;466: 57–62. doi: 10.1016/s1383-5718(00)00003-6 10751726

65. Kilic AO, Pavlova SI, Alpay S, Kilic SS, Tao L. Comparative Study of Vaginal Lactobacillus Phages Isolated from Women in the United States and Turkey: Prevalence, Morphology, Host Range, and DNA Homology. Clin Diagn Lab Immunol. 2001;8: 31–39. doi: 10.1128/CDLI.8.1.31-39.2001 11139192

66. Martín R, Soberón N, Escobedo S, Suárez JE. Bacteriophage induction versus vaginal homeostasis: role of H2O2 in the selection of Lactobacillus defective prophages. Int Microbiol. 2009;12: 131–136. doi: 10.2436/20.1501.01.90 19784933

67. Dausset C, Patrier S, Gajer P, Thoral C, Lenglet Y, Cardot J, et al. Comparative phase I randomized open-label pilot clinical trial versus slow release muco-adhesive tablets. Eur J Clin Microbiol Infect Dis. 2018.

68. Barnabas SL, Dabee S, Passmore JS, Jaspan HB, Lewis DA, Jaumdally SZ, et al. Converging epidemics of sexually transmitted infections and bacterial vaginosis in southern African female adolescents at risk of HIV. Int J STD AIDS. 2017;0: 1–9. doi: 10.1177/0956462417740487 29198180

69. Weisburg WG, Barns SM, Pelletier DA, Lane DJ. 16S ribosomal DNA amplification for phylogenetic study. J Bacteriol. 1991;173: 697–703. doi: 10.1128/jb.173.2.697-703.1991 1987160

70. Bolger AM, Lohse M, Usadel B. Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics. 2014/04/01. 2014;30: 2114–2120. doi: 10.1093/bioinformatics/btu170 24695404

71. Bankevich A, Nurk S, Antipov D, Gurevich AA, Dvorkin M, Kulikov AS, et al. SPAdes: a new genome assembly algorithm and its applications to single-cell sequencing. J Comput Biol. 2012/04/16. 2012;19: 455–477. doi: 10.1089/cmb.2012.0021 22506599

72. Kosugi S, Hirakawa H, Tabata S. GMcloser: closing gaps in assemblies accurately with a likelihood-based selection of contig or long-read alignments. Bioinformatics. 2015;31: 3733–3741. doi: 10.1093/bioinformatics/btv465 26261222

73. Gurevich A, Saveliev V, Vyahhi N, Tesler G. QUAST: quality assessment tool for genome assemblies. Bioinformatics. 2013;29: 1072–1075. doi: 10.1093/bioinformatics/btt086 23422339

74. Overbeek R, Olson R, Pusch GD, Olsen GJ, Davis JJ, Disz T, et al. The SEED and the Rapid Annotation of microbial genomes using Subsystems Technology (RAST). Nucleic Acids Res. 2013/11/29. 2014;42: D206–D214. doi: 10.1093/nar/gkt1226 24293654

75. Zankari E, Hasman H, Cosentino S, Vestergaard M, Rasmussen S, Lund O, et al. Identification of acquired antimicrobial resistance genes. J Antimicrob Chemother. 2012/07/10. 2012;67: 2640–2644. doi: 10.1093/jac/dks261 22782487

76. Alcock BP, Raphenya AR, Lau TTY, Tsang KK, Bouchard M, Edalatmand A, et al. CARD 2020: antibiotic resistome surveillance with the comprehensive antibiotic resistance database. Nucleic Acids Res. 2019;48: D517–D525. doi: 10.1093/nar/gkz935 31665441

77. Feldgarden M, Brover V, Haft DH, Prasad AB, Slotta DJ, Tolstoy I, et al. Validating the AMRFinder Tool and Resistance Gene Database by Using Antimicrobial Resistance Genotype-Phenotype Correlations in a Collection of Isolates. Antimicrob Agents Chemother. 2019;63: e00483–19. doi: 10.1128/AAC.00483-19 31427293

78. Arndt D, Grant JR, Marcu A, Sajed T, Pon A, Liang Y, et al. PHASTER: a better, faster version of the PHAST phage search tool. Nucleic Acids Res. 2016;44: 16–21. doi: 10.1093/nar/gkw387 27141966

79. Couvin D, Bernheim A, Toffano-Nioche C, Touchon M, Michalik J, Néron B, et al. CRISPRCasFinder, an update of CRISRFinder, includes a portable version, enhanced performance and integrates search for Cas proteins. Nucleic Acids Res. 2018;46: W246–W251. doi: 10.1093/nar/gky425 29790974

80. Biswas A, Gagnon JN, Brouns SJJ, Fineran PC, Brown CM. CRISPRTarget: bioinformatic prediction and analysis of crRNA targets. RNA Biol. 2013/03/14. 2013;10: 817–827. doi: 10.4161/rna.24046 23492433

81. Columb MO, Sagadai S. Multiple comparisons. Curr Anaesth Crit Care. 2006;17: 233–236.doi:https://doi.org/10.1016/j.cacc.2006.03.005

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