Development and selection of low-level multi-drug resistance over an extended range of sub-inhibitory ciprofloxacin concentrations in Escherichia coli.
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
29 05 2020
29 05 2020
Historique:
received:
02
12
2019
accepted:
30
04
2020
entrez:
31
5
2020
pubmed:
31
5
2020
medline:
15
12
2020
Statut:
epublish
Résumé
To better combat bacterial antibiotic resistance, a growing global health threat, it is imperative to understand its drivers and underlying biological mechanisms. One potential driver of antibiotic resistance is exposure to sub-inhibitory concentrations of antibiotics. This occurs in both the environment and clinic, from agricultural contamination to incorrect dosing and usage of poor-quality medicines. To better understand this driver, we tested the effect of a broad range of ciprofloxacin concentrations on antibiotic resistance development in Escherichia coli. We observed the emergence of stable, low-level multi-drug resistance that was both time and concentration dependent. Furthermore, we identified a spectrum of single mutations in strains with resistant phenotypes, both previously described and novel. Low-level class-wide resistance, which often goes undetected in the clinic, may allow for bacterial survival and establishment of a reservoir for outbreaks of high-level antibiotic resistant infections.
Identifiants
pubmed: 32471975
doi: 10.1038/s41598-020-65602-z
pii: 10.1038/s41598-020-65602-z
pmc: PMC7260183
doi:
Substances chimiques
DNA, Bacterial
0
Ciprofloxacin
5E8K9I0O4U
Types de publication
Comparative Study
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
8754Références
Hughes, D. & Andersson, D. I. Selection of resistance at lethal and non-lethal antibiotic concentrations. Curr. Opin. Microbiol. 15, 555–560 (2012).
pubmed: 22878455
doi: 10.1016/j.mib.2012.07.005
Wei, R., Ge, F., Chen, M. & Wang, R. Occurrence of ciprofloxacin, enrofloxacin, and florfenicol in animal wastewater and water resources. J. Environ. Qual. 41, 1481–1486 (2012).
pubmed: 23099939
doi: 10.2134/jeq2012.0014
Sukul, P. & Spiteller, M. Fluoroquinoloe Antibiotics in the Environment. in Reviews of Environmental Contamination and Toxicology 131–162 (2007).
Fisher, H. et al. Continuous low-dose antibiotic prophylaxis for adults with repeated urinary tract infections (AnTIC): a randomised, open-label trial. Lancet Infect. Dis. 18, 957–968 (2018).
pubmed: 30037647
pmcid: 6105581
doi: 10.1016/S1473-3099(18)30279-2
Kelesidis, T. & Falagas, E. Substandard / Counterfeit Antimicrobial Drugs. 28, 443–464 (2015).
Andersson, D. I. & Hughes, D. Microbiological effects of sublethal levels of antibiotics. Nat. Rev. Microbiol. 12, 465–478 (2014).
pubmed: 24861036
doi: 10.1038/nrmicro3270
Wistrand-Yuen, E. et al. Evolution of high-level resistance during low-level antibiotic exposure. Nat. Commun. 9 (2018).
Bai, H. et al. Analysis of mechanisms of resistance and tolerance of Escherichia coli to enrofloxacin. Ann. Microbiol. 62, 293–298 (2012).
doi: 10.1007/s13213-011-0260-3
Boos, M. et al. In vitro development of resistance to six quinolones in Streptococcus pneumoniae, Streptococcus pyogenes, and Staphylococcus aureus. Antimicrob. Agents Chemother. 45, 938–942 (2001).
pubmed: 11181385
pmcid: 90398
doi: 10.1128/AAC.45.3.938-942.2001
Browne, F. A. et al. Single and multi-step resistance selection study in Streptococcus pneumoniae comparing ceftriaxone with levofloxacin, gatifloxacin and moxifloxacin. Int. J. Antimicrob. Agents 20, 93–99 (2002).
pubmed: 12297357
doi: 10.1016/S0924-8579(02)00120-6
Davies, T. A., Pankuch, G. A., Dewasse, B. E., Jacobs, M. R. & Appelbaum, P. C. In vitro development of resistance to five quinolones and amoxicillin-clavulanate in Streptococcus pneumoniae. Antimicrob. Agents Chemother. 43, 1177–1182 (1999).
pubmed: 10223932
pmcid: 89129
doi: 10.1128/AAC.43.5.1177
Ching, C., Orubu, E. S. F., Wirtz, V. J. & Zaman, M. H. Bacterial antibiotic resistance development and mutagenesis following exposure to subminimal inhibitory concentrations of fluoroquinolones in vitro: a systematic literature review protocol. BMJ Open 1–6. https://doi.org/10.1136/bmjopen-2019-030747 (2019)
pubmed: 31666265
pmcid: 6830604
doi: 10.1136/bmjopen-2019-030747
Aldridge, K. E. et al. Lomefloxacin, a new fluoroquinolone. Studies on in vitro antimicrobial spectrum, potency, and development of resistance. Diagn. Microbiol. Infect. Dis. 12, 221–233 (1989).
pubmed: 2791485
doi: 10.1016/0732-8893(89)90019-9
Avrain, L. et al. Selection of quinolone resistance in Streptococcus pneumoniae exposed in vitro to subinhibitory drug concentrations. J Antimicrob Chemother 60, 965–972 (2007).
pubmed: 17693451
doi: 10.1093/jac/dkm292
Barry, A. L. & Jones, R. N. Cross-resistance among cinoxacin, ciprofloxacin, DJ-6783, enoxacin, nalidixic acid, norfloxacin, and oxolinic acid after in vitro selection of resistant populations. Antimicrob. Agents Chemother. 25, 775–777 (1984).
pubmed: 6234858
pmcid: 185641
doi: 10.1128/AAC.25.6.775
Jonas, D. et al. Development and mechanism of fluoroquinolone resistance in Legionella pneumophila. J. Antimicrob. Chemother. 51, 275–280 (2003).
pubmed: 12562691
doi: 10.1093/jac/dkg054
Weir, R. et al. Variability in the content of Indian generic ciprofloxacin eye drops. 1094–1096, https://doi.org/10.1136/bjo.2004.059519 (2005)
pubmed: 16113355
doi: 10.1136/bjo.2004.059519
Frimpong, G. et al. Quality Assessment of Some Essential Children’s Medicines Sold in Licensed Outlets in Ashanti Region, Ghana. 2018 (2018).
Tabernero, P. et al. A random survey of the prevalence of falsified and substandard antibiotics in the Lao PDR. J. Antimicrob. Chemother. 74, 2417–2425 (2019).
pubmed: 31049576
pmcid: 6640311
doi: 10.1093/jac/dkz164
Kim, E. S. & Hooper, D. C. Clinical importance and epidemiology of quinolone resistance. Infect. Chemother. 46, 226–238 (2014).
pubmed: 25566402
pmcid: 4285002
doi: 10.3947/ic.2014.46.4.226
McEwen, S. A. & Fedorka-Cray, P. J. Antimicrobial Use and Resistance in Animals. Clin. Infect. Dis. 34, Supplement (2002).
Acar, J. F. & Goldstein, F. W. Trends in Bacterial Resistance to Fluoroquinolones. Clin. Infect. Dis., 24 (1999).
Dalhoff, A. Global Fluoroquinolone Resistance Epidemiology and Implictions for Clinical Use. Interdiscip. Persepctives Infect. Dsiseases 2012 (2012).
doi: 10.1155/2012/976273
Zayed, A. A. F., Essam, T. M., Hashem, A. G. M. & El-Tayeb, O. M. ‘Supermutators’ found amongst highly levofloxacin-resistant E. coli isolates: A rapid protocol for the detection of mutation sites. Emerg. Microbes Infect. 4 (2015).
Clerch, B., Bravo, J. M. & Llagostera, M. Analysis of the ciprofloxacin-induced mutations in Salmonella typhimurium. Environ. Mol. Mutagen. 27, 110–115 (1996).
pubmed: 8603664
doi: 10.1002/(SICI)1098-2280(1996)27:2<110::AID-EM6>3.0.CO;2-K
Isom, G. L. et al. MCE domain proteins: Conserved inner membrane lipid-binding proteins required for outer membrane homeostasis. Sci. Rep. 7, 1–12 (2017).
doi: 10.1038/s41598-017-09111-6
Matern, Y., Barion, B. & Behrens-Kneip, S. PpiD is a player in the network of periplasmic chaperones in Escherichia coli. BMC Microbiol. 10 (2010).
Mustaev, A. et al. Fluoroquinolone-gyrase-DNA complexes two modes of drug binding. J. Biol. Chem. 289, 12300–12312 (2014).
pubmed: 24497635
pmcid: 4007428
doi: 10.1074/jbc.M113.529164
Hooper, D. C. Emerging mechanisms of fluoroquinolone resistance. Emerg. Infect. Dis. 7, 337–341 (2001).
pubmed: 11294736
pmcid: 2631735
doi: 10.3201/eid0702.010239
Van Der Putten, B. C. L. et al. Quantifying the contribution of four resistance mechanisms to ciprofloxacin MIC in Escherichia coli: A systematic review. J. Antimicrob. Chemother. 74, 298–310 (2019).
pubmed: 30357339
doi: 10.1093/jac/dky417
Corbett, K. D., Shultzaberger, R. K. & Berger, J. M. The C-terminal domain of DNA gyrase A adopts a DNA-bending β-pinwheel fold. Proc. Natl. Acad. Sci. USA 101, 7293–7298 (2004).
pubmed: 15123801
doi: 10.1073/pnas.0401595101
Weigel, L. M., Steward, C. D. & Tenover, F. C. gyrA mutations associated with fluoroquinolone resistance in eight species of Enterobacteriaceae. Antimicrob. Agents Chemother. 42, 2661–2667 (1998).
pubmed: 9756773
pmcid: 105915
doi: 10.1128/AAC.42.10.2661
Willmott, C. J. R. & Maxwell, A. A single point mutation in the DNA gyrase A protein greatly reduces binding of fluoroquinolones to the gyrase-DNA complex. Antimicrob. Agents Chemother. 37, 126–127 (1993).
pubmed: 8381633
pmcid: 187618
doi: 10.1128/AAC.37.1.126
Du, D. et al. Multidrug efflux pumps: structure, function and regulation. Nat. Rev. Microbiol. 16, 523–539 (2018).
pubmed: 30002505
doi: 10.1038/s41579-018-0048-6
Yu, E. W., Aires, J. R. & Nikaido, H. AcrB multidrug efflux pump of Escherichia coli: Composite substrate-binding cavity of exceptional flexibility generates its extremely wide substrate specificity. J. Bacteriol. 185, 5657–5664 (2003).
pubmed: 13129936
pmcid: 193975
doi: 10.1128/JB.185.19.5657-5664.2003
Okusu, H., Ma, D. & Nikaido, H. AcrAB efflux pump plays a major role in the antibiotic resistance phenotype of Escherichia coli multiple-antibiotic-resistance (Mar) mutants. J. Bacteriol. 178, 306–308 (1996).
pubmed: 8550435
pmcid: 177656
doi: 10.1128/JB.178.1.306-308.1996
Ma, D., Alberti, M., Lynch, C., Nikaido, H. & Hearst, J. E. The local repressor AcrR plays a modulating role in the regulation of acrAB genes of Escherichia coli by global stress signals. Mol. Microbiol. 19, 101–112 (1996).
pubmed: 8821940
doi: 10.1046/j.1365-2958.1996.357881.x
Gambino, L., Gracheck, S. J. & Miller, P. F. Overexpression of the marA positive regulator is sufficient to confer multiple antibiotic resistance in Escherichia coli. J. Bacteriol. 175, 2888–2894 (1993).
pubmed: 8491710
pmcid: 204606
doi: 10.1128/JB.175.10.2888-2894.1993
Cohen, S. P., Hachler, H. & Levy, S. B. Genetic and functional analysis of the multiple antibiotic resistance (mar) locus in Escherichia coli. J. Bacteriol. 175, 1484–1492 (1993).
pubmed: 8383113
pmcid: 193236
doi: 10.1128/JB.175.5.1484-1492.1993
Goldman, J. D., White, D. G. & Levy, S. B. Multiple antibiotic resistance (mar) locus protects Escherichia coli from rapid cell killing by fluoroquinolones. Antimicrob. Agents Chemother. 40, 1266–1269 (1996).
pubmed: 8723480
pmcid: 163305
doi: 10.1128/AAC.40.5.1266
Li, M. et al. Crystal Structure of the Transcriptional Regulator AcrR from Escherichia coli. J. Mol. Biol. 374, 591–603 (2007).
pubmed: 17950313
pmcid: 2254304
doi: 10.1016/j.jmb.2007.09.064
Adler, M., Anjum, M., Andersson, D. I. & Sandegren, L. Combinations of mutations in envZ, ftsI, mrdA, acrB and acrR can cause high-level carbapenem resistance in Escherichia coli. J. Antimicrob. Chemother. 71, 1188–1198 (2016).
pubmed: 26869688
doi: 10.1093/jac/dkv475
Alekshun, M. N., Levy, S. B., Mealy, T. R., Seaton, B. A. & Head, J. F. The crystal structure of MarR, a regulator of multiple antibiotic resistance, at 2.3 Å resolution. Nat. Struct. Biol. 8, 710–714 (2001).
pubmed: 11473263
doi: 10.1038/90429
Duval, V., McMurry, L. M., Foster, K., Head, J. F. & Levy, S. B. Mutational analysis of the multiple-antibiotic resistance regulator marR reveals a ligand binding pocket at the interface between the dimerization and DNA binding domains. J. Bacteriol. 195, 3341–3351 (2013).
pubmed: 23687277
pmcid: 3719538
doi: 10.1128/JB.02224-12
Alekshun, M. N., Kim, Y. S. & Levy, S. B. Mutational analysis of MarR, the negative regulator of marRAB expression in Escherichia coli, suggests the presence of two regions required for DNA binding. Mol. Microbiol. 35, 1394–1404 (2000).
pubmed: 10760140
doi: 10.1046/j.1365-2958.2000.01802.x
Lindgren, P. K., Karlsson, Å. & Hughes, D. Mutation rate and evolution of fluoroquinolone resistance in Escherichia coli isolates from patients with urinary tract infections. Antimicrob. Agents Chemother. 47, 3222–3232 (2003).
doi: 10.1128/AAC.47.10.3222-3232.2003
Kern, W. V., Oethinger, M., Jellen-Ritter, A. S. & Levy, S. B. Non-target gene mutations in the development of fluoroquinolone resistance in Escherichia coli. Antimicrob. Agents Chemother. 44, 814–820 (2000).
pubmed: 10722475
pmcid: 89776
doi: 10.1128/AAC.44.4.814-820.2000
Lázár, V. et al. Genome-wide analysis captures the determinants of the antibiotic cross-resistance interaction network. Nat. Commun. 5 (2014).
Alzrigat, L. P., Huseby, D. L., Brandis, G. & Hughes, D. Fitness cost constrains the spectrum of marR mutations in ciprofloxacin-resistant Escherichia coli. J. Antimicrob. Chemother. 72, 3016–3024 (2017).
doi: 10.1093/jac/dkx270
Shoji, S., Dambacher, C. M., Shajani, Z. & Williamson, J. R. Systemic Deletion of Ribosome Assembly Genes in E. Coli. 413, 751–761 (2013).
Huseby, D. L. et al. Mutation Supply and Relative Fitness Shape the Genotypes of Ciprofloxacin-Resistant Escherichia coli. Mol. Biol. Evol. 34, 1029–1039 (2017).
pubmed: 28087782
pmcid: 5400412
Liu, J., Gefen, O., Ronin, I., Bar-Meir, M. & Balaban, N. Q. Effect of tolerance on the evolution of antibiotic resistance under drug combinations. Science 367, 200–204 (2020).
pubmed: 31919223
Oethinger, M., Podglajen, I., Kern, W. V. & Levy, S. B. Overexpression of the marA or soxS regulatory gene in clinical topoisomerase mutants of Escherichia coli. Antimicrob. Agents Chemother. 42, 2089–2094 (1998).
pubmed: 9687412
pmcid: 105868
doi: 10.1128/AAC.42.8.2089
Baquero, F. Low-level antibacterial resistance: A gateway to clinical resistance. Drug Resist. Updat. 4, 93–105 (2001).
pubmed: 11512526
doi: 10.1054/drup.2001.0196
Morgan-Linnell, S. K., Boyd, L. B., Steffen, D. & Zechiedrich, L. Mechanisms accounting for fluoroquinolone resistance in Escherichia coli clinical isolates. Antimicrob. Agents Chemother. 53, 235–241 (2009).
pubmed: 18838592
doi: 10.1128/AAC.00665-08
Szili, P. et al. Rapid Evolution of Reduced Susceptibility against a Balanced Dual-Targeting Antibiotic through Stepping-Stone Mutations. 63, 1–15 (2019).
Ahmed, A. M., Miyoshi, S. I., Shinoda, S. & Shimamoto, T. Molecular characterization of a multidrug-resistant strain of enteroinvasive Escherichia coli O164 isolated in Japan. J. Med. Microbiol. 54, 273–278 (2005).
pubmed: 15713611
doi: 10.1099/jmm.0.45908-0
Paniagua-Contreras, G. L. et al. Whole-genome sequence analysis of multidrug-resistant uropathogenic strains of Escherichia coli from Mexico. Infect. Drug Resist. 12, 2363–2377 (2019).
pubmed: 31447566
pmcid: 6682767
doi: 10.2147/IDR.S203661
Komp Lindgren, P., Marcusson, L. L., Sandvang, D. & Hughes, D. Biological Cost of Single and Multiple Norfloxacin Resistance Mutations in. Antimicrob Agents Chemother 49, 2343–2351 (2005).
pubmed: 15917531
doi: 10.1128/AAC.49.6.2343-2351.2005
Suzuki, S., Horinouchi, T. & Furusawa, C. Prediction of antibiotic resistance by gene expression profiles. Nat. Commun. 5, 1–12 (2014).
Chantell, C., Humphries, R. M. & Lewis, J. S. Fluoroquinolone Breakpoints for Enterobacteriaceae and Pseudomonas aeruginosa CLSI rationale document MR02 Oregon Health and Science University. (2019).
Wang, Q. et al. Enhancement of biofilm formation by subinhibitory concentrations of macrolides in icaADBC-positive and -negative clinical isolates of Staphylococcus epidermidis. Antimicrob. Agents Chemother. 54, 2707–2711 (2010).
pubmed: 20231401
pmcid: 2876384
doi: 10.1128/AAC.01565-09
Andrews, J. M. Determination of minimum inhibitory concentrations. J. Antimicrob. Chemother. 5–16 (2001).
pubmed: 11420333
doi: 10.1093/jac/48.suppl_1.5
Brewster, J. D. A simple micro-growth assay for enumerating bacteria. J. Microbiol. Methods 53, 77–86 (2003).
pubmed: 12609726
doi: 10.1016/S0167-7012(02)00226-9
Shakeri, H. et al. Establishing statistical equivalence of data from different sampling approaches for assessment of bacterial phenotypic antimicrobial resistance. Appl. Environ. Microbiol. 84, 1–16 (2018).
doi: 10.1128/AEM.02724-17