Abstract
Campylobacter jejuni is a foodborne pathogen that causes gastroenteritis in humans and has developed resistance to various antibiotics. The primary objective of this research was to examine the network of antibiotic resistance in C. jejuni. The study involved the wild and antibiotic-resistant strains placed in the presence and absence of antibiotics to review their gene expression profiles in response to ciprofloxacin via microarray. Differentially expressed genes (DEGs) analysis and Protein–Protein Interaction (PPI) Network studies were performed for these genes. The results showed that the resistance network of C. jejuni is modular, with different genes involved in bacterial motility, capsule synthesis, efflux, and amino acid and sugar synthesis. Antibiotic treatment resulted in the down-regulation of cluster genes related to translation, flagellum formation, and chemotaxis. In contrast, cluster genes involved in homeostasis, capsule formation, and cation efflux were up-regulated. The study also found that macrolide antibiotics inhibit the progression of C. jejuni infection by inactivating topoisomerase enzymes and increasing the activity of epimerase enzymes, trying to compensate for the effect of DNA twisting. Then, the bacterium limits the movement to conserve energy. Identifying the antibiotic resistance network in C. jejuni can aid in developing drugs to combat these bacteria. Genes involved in cell division, capsule formation, and substance transport may be potential targets for inhibitory drugs. Future research must be directed toward comprehending the underlying mechanisms contributing to the modularity of antibiotic resistance and developing strategies to disrupt and mitigate the growing threat of antibiotic resistance effectively.
Similar content being viewed by others
Availability of data and materials
All the data produced for this manuscript will be available upon request to the corresponding author.
Code availability
Not applicable. The model and computational framework produced for this manuscript mentioned in the manuscript otherwise will be available upon request to the corresponding author.
References
Aleksić E, Miljković-Selimović B, Tambur Z et al (2021) Resistance to antibiotics in thermophilic campylobacters. Front Med 8:763434. https://doi.org/10.3389/fmed.2021.763434
Campos MA, Vargas MA, Regueiro V et al (2004) Capsule polysaccharide mediates bacterial resistance to antimicrobial peptides. Infect Immun 72:7107–7114. https://doi.org/10.1128/IAI.72.12.7107-7114.2004
Carrillo CD, Taboada E, Nash JHE et al (2004) Genome-wide expression analyses of Campylobacter jejuni NCTC11168 reveals coordinate regulation of motility and virulence by flhA. J Biol Chem 279:20327–20338. https://doi.org/10.1074/jbc.M401134200
Cayrou C, Barratt NA, Ketley JM, Bayliss CD (2021) Phase variation during host colonization and invasion by Campylobacter jejuni and other campylobacter species. Front Microbiol 12:705139. https://doi.org/10.3389/fmicb.2021.705139
Dahl LG, Joensen KG, Østerlund MT et al (2021) Prediction of antimicrobial resistance in clinical Campylobacter jejuni isolates from whole-genome sequencing data. Eur J Clin Microbiol Infect Dis 40:673–682. https://doi.org/10.1007/s10096-020-04043-y
Dasti JI, Tareen AM, Lugert R et al (2010) Campylobacter jejuni: a brief overview on pathogenicity-associated factors and disease-mediating mechanisms. Int J Med Microbiol 300:205–211. https://doi.org/10.1016/j.ijmm.2009.07.002
Elmi A, Nasher F, Dorrell N et al (2021) Revisiting Campylobacter jejuni virulence and fitness factors: role in sensing, adapting, and competing. Front Cell Infect Microbiol 10:1–15. https://doi.org/10.3389/fcimb.2020.607704
Franco M, Vivo J-M (2019) Cluster analysis of microarray data. In: Bolón-Canedo V, Alonso-Betanzos A (eds) Microarray bioinformatics. Springer, New York, NY, pp 153–183
García-Sánchez L, Melero B, Rovira J (2018) Campylobacter in the Food Chain. Adv Food Nutr Res 86:215–252. https://doi.org/10.1016/bs.afnr.2018.04.005
Gibreel A, Taylor DE (2006) Macrolide resistance in Campylobacter jejuni and Campylobacter coli. J Antimicrob Chemother 58:243–255. https://doi.org/10.1093/jac/dkl210
Guerry P (2007) Campylobacter flagella: not just for motility. Trends Microbiol 15:456–461. https://doi.org/10.1016/j.tim.2007.09.006
Guerry P, Poly F, Riddle M et al (2012) Campylobacter polysaccharide capsules: virulence and vaccines. Front Cell Infect Microbiol 2:7. https://doi.org/10.3389/fcimb.2012.00007
Gundogdu O (2011) Re-annotation of the Campylobacter jejuni NCTC11168 genome and functional characterisation of selected genes involved in strain pathogenesis. Doctoral Dissertation, London School of Hygiene & Tropical Medicine
Haddad N, Marce C, Magras C, Cappelier JM (2010) An overview of methods used to clarify pathogenesis mechanisms of Campylobacter jejuni. J Food Prot 73:786–802. https://doi.org/10.4315/0362-028X-73.4.786
Hyytiäinen H, Juntunen P, Scott T et al (2013) Effect of ciprofloxacin exposure on DNA repair mechanisms in Campylobacter jejuni. Microbiology (united Kingdom) 159:2513–2523. https://doi.org/10.1099/mic.0.069203-0
Iovine NM (2013) Resistance mechanisms in Campylobacter jejuni. Virulence 4:230–240. https://doi.org/10.4161/viru.23753
Jin S, Joe A, Lynett J et al (2001) JlpA, a novel surface-exposed lipoprotein specific to Campylobacter jejuni, mediates adherence to host epithelial cells. Mol Microbiol 39(5):1225–1236. https://doi.org/10.1111/j.1365-2958.2001.02294.x
Kanehisa M, Goto S, Kawashima S, Nakaya A (2002) The KEGG databases at GenomeNet. Nucleic Acids Res 30:42–46. https://doi.org/10.1093/nar/30.1.42
Khan JA, Abulreesh HH, Kumar R et al (2019) Antibiotic resistance in Campylobacter jejuni: mechanism, status, and public health significance. In: Ahmad I, Ahmad S, Rumbaugh KP (eds) Antibacterial drug discovery to combat MDR: natural compounds, nanotechnology and novel synthetic sources. Springer, Singapore, pp 95–114. https://doi.org/10.1007/978-981-13-9871-1_4
Konkel ME, Garvis SG, Tipton SL et al (1997) Identification and molecular cloning of a gene encoding a fibronectin-binding protein (CadF) from Campylobacter jejuni. Mol Microbiol 24:953–963. https://doi.org/10.1046/j.1365-2958.1997.4031771.x
Kreutzberger MAB, Ewing C, Poly F et al (2020) Atomic structure of the Campylobacter jejuni flagellar filament reveals how ε Proteobacteria escaped Toll-like receptor 5 surveillance. Proc Natl Acad Sci USA 117(29):16985–16991. https://doi.org/10.1073/pnas.2010996117
Kristich CJ, Ordal GW (2002) Bacillus subtilis CheD is a chemoreceptor modification enzyme required for chemotaxis. J Biol Chem 277:25356–25362. https://doi.org/10.1074/jbc.M201334200
Lai YW, Ridone P, Peralta G et al (2020) Evolution of the stator elements of rotary prokaryote motors. J Bacteriol 202:e00557-e619. https://doi.org/10.1128/JB.00557-19
Lin X, Xu S, Yang Y et al (2009) Purification and characterization of anthranilate synthase component I ( TrpE ) from Mycobacterium tuberculosis H37Rv. Protein Expr Purif 64:8–15. https://doi.org/10.1016/j.pep.2008.09.020
Mandal RK, Jiang T, Kwon YM (2017) Essential genome of Campylobacter jejuni. BMC Genomics 18:616. https://doi.org/10.1186/s12864-017-4032-8
Morimoto YV, Minamino T (2014) Structure and function of the bi-directional bacterial flagellar motor. Biomolecules 4:217–234. https://doi.org/10.3390/biom4010217
Naumov V, Balashov I, Lagutin V et al (2017) VolcanoR—web service to produce volcano plots and do basic enrichment analysis. bioRxiv. https://doi.org/10.1101/165100
Nordmann E, McAleer P, Toivo W et al (2022) Data visualization using R for researchers who do not use R. Adv Methods Pract Psychol Sci. https://doi.org/10.1177/25152459221074654
Padan E, Venturi M, Gerchman Y, Dover N (2001) Na+/H+ antiporters. Biochim Biophys Acta 1505:144–157. https://doi.org/10.1016/S0005-2728(00)00284-X
Page WJ, Huyer G, Huyer M, Worobec EA (1989) Characterization of the Porins of Campylobacter jejuni and Campylobacter coli and implications for antibiotic susceptibility. Antimicrob Agents Chemother 33:297–303. https://doi.org/10.1128/AAC.33.3.297
Parkhill J, Wren BW, Mungall K et al (2000) The genome sequence of the foodborne pathogen Campylobacter jejuni reveals hypervariable sequences. Nature 403:665–668. https://doi.org/10.1038/35001088
Poly F, Threadgill D, Stintzi A (2005) Genomic diversity in Campylobacter jejuni: identification of C. jejuni 81–176-specific genes. J Clin Microbiol 43:2330–2338. https://doi.org/10.1128/JCM.43.5.2330-2338.2005
Reid AN, Pandey R, Palyada K et al (2008) Identification of Campylobacter jejuni genes contributing to acid adaptation by transcriptional profiling and genome-wide mutagenesis. Appl Environ Microbiol 74:1598–1612. https://doi.org/10.1128/AEM.01508-07
Riegert AS, Raushel FM (2021) Functional and structural characterization of the UDP-glucose dehydrogenase involved in capsular polysaccharide biosynthesis from Campylobacter jejuni. Biochemistry 60:725–734. https://doi.org/10.1021/acs.biochem.0c00953
Salusso A, Raimunda D (2017) Defining the roles of the cation diffusion facilitators in Fe2+/Zn2+ homeostasis and establishment of their participation in virulence in Pseudomonas aeruginosa. Front Cell Infect Microbiol 7:84. https://doi.org/10.3389/fcimb.2017.00084
Santiveri M, Roa-Eguiara A, Kühne C et al (2020) Structure and function of stator units of the bacterial flagellar motor. Cell 183:244-257.e16. https://doi.org/10.1016/j.cell.2020.08.016
Silander KM, Pihlajamaa P, Sahu B et al (2017) Characterization of an androgen-responsive, ornithine decarboxylase-related protein in mouse kidney. Biosci Rep 37:BSR20170163. https://doi.org/10.1042/BSR20170163
Song WS, Jeon YJ, Namgung B et al (2017) A conserved TLR5 binding and activation hot spot on flagellin. Sci Rep 7:1–11. https://doi.org/10.1038/srep40878
Sun L, Zhou F, Shao Y et al (2020) The iron–sulfur protein subunit of succinate dehydrogenase is critical in driving mitochondrial reactive oxygen species generation in Apostichopus japonicus. Fish Shellfish Immunol 102:350–360. https://doi.org/10.1016/j.fsi.2020.04.060
Szklarczyk D, Kirsch R, Koutrouli M et al (2023) The STRING database in 2023: protein-protein association networks and functional enrichment analyses for any sequenced genome of interest. Nucleic Acids Res 51:D638–D646. https://doi.org/10.1093/nar/gkac1000
Szurmant H, Ordal GW (2004) Diversity in chemotaxis mechanisms among the bacteria and archaea. Microbiol Mol Biol Rev 68:301–319. https://doi.org/10.1128/MMBR.68.2.301-319.2004
Szurmant H, Bunn MW, Cannistraro VJ, Ordal GW (2003) Bacillus subtilis hydrolyzes CheY-P at the location of its action, the flagellar switch. J Biol Chem 278:48611–48616. https://doi.org/10.1074/jbc.M306180200
Szurmant H, Muff TJ, Ordal GW (2004) Bacillus subtilis CheC and FliY are members of a novel class of CheY-P-hydrolyzing proteins in the chemotactic signal transduction cascade. J Biol Chem 279:21787–21792. https://doi.org/10.1074/jbc.M311497200
Tang Z, Li C, Kang B et al (2017) GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res 45:W98–W102. https://doi.org/10.1093/nar/gkx247
Thalamuthu A, Mukhopadhyay I, Zheng X, Tseng GC (2006) Evaluation and comparison of gene clustering methods in microarray analysis. Bioinformatics 22:2405–2412. https://doi.org/10.1093/bioinformatics/btl406
van Putten JP, van Alphen LB, Wösten MM, de Zoete MR (2009) Molecular mechanisms of campylobacter infection. Curr Top Microbiol Immunol. 337:197–229. https://doi.org/10.1007/978-3-642-01846-6_7
Vaara M (1993) Outer membrane permeability barrier to azithromycin, clarithromycin, and roxithromycin in gram-negative enteric bacteria. Antimicrob Agents Chemother 37:354–356. https://doi.org/10.1128/AAC.37.2.354
Wu Z, Periaswamy B, Sahin O et al (2016) Point mutations in the major outer membrane protein drive hypervirulence of a rapidly expanding clone of Campylobacter jejuni. Proc Natl Acad Sci U S A 113:10690–10695. https://doi.org/10.1073/pnas.1605869113
Zhao S, Guo Y, Sheng Q, Shyr Y (2014) Advanced heat map and clustering analysis using heatmap3. Biomed Res Int 2014:986048. https://doi.org/10.1155/2014/986048
Ziprin RL, Young CR, Byrd JA et al (2001) Role of campylobacter jejuni potential virulence genes in cecal colonization. Avian Dis 45:549–557. https://doi.org/10.2307/1592894
Funding
The authors declare that no funds, grants, or other support was received during the preparation of this manuscript.
Author information
Authors and Affiliations
Contributions
All authors contributed to the study’s conception and design. The model and the computational framework were designed by all authors, who also conducted data analysis. HR, NG, and ASHH were responsible for material preparation, data collection, and analysis. The initial manuscript draft was written by HR, with input and comments from all authors. All authors reviewed and approved the final version of the manuscript. EM, MA, and DFY provided valuable feedback that influenced the development of the research, analysis, and manuscript. They also contributed significantly to resolving technical aspects of the study.
Corresponding author
Ethics declarations
Conflict of interest
The authors have no relevant financial or non-financial interests to disclose.
Ethics approval
It does not apply to the biological samples. All computational activities were conducted via free version software or package.
Consent to participate
Each author acknowledges that he/she has participated in the work substantively and prepared to take full responsibility.
Consent for publication
The authors have given their permission to submit this manuscript in this present format following the author guidelines of "Archives of Microbiology".
Additional information
Communicated by Yusuf Akhter.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Rezayatmand, H., Golestani, N., Haghighat Hoseini, A.S. et al. Gene expression profile of Campylobacter jejuni in response to macrolide antibiotics. Arch Microbiol 206, 117 (2024). https://doi.org/10.1007/s00203-024-03849-0
Received:
Revised:
Accepted:
Published:
DOI: https://doi.org/10.1007/s00203-024-03849-0