Ciprofloxacin interferes with Salmonella Typhimurium intracellular survival and host virulence through repression of Salmonella pathogenicity island-2 (SPI-2) genes expression.

Current study aims to characterize influence of sub-minimum inhibitory concentration (sub-MIC) of ciprofloxacin on Salmonella intracellular survival and host virulence. Herein, Salmonella resistance patterns to various antibiotics were in agreement with those reported in previous studies. Moreover, intracellular survival of both ciprofloxacin-sensitive and -resistant Salmonella was markedly reduced upon treatment with sub-MIC of ciprofloxacin as determined by gentamicin protection assay. These findings were further confirmed using immunostaining indicating an inhibitory effect of sub-MIC of ciprofloxacin on Salmonella intracellular survival. RT-qPCR revealed that expression of genes encoding Salmonella type three secretion system (TTSS) decreased upon bacterial exposure to sub-MIC of ciprofloxacin. Furthermore, bacterial exposure to sub-MIC of ciprofloxacin significantly reduced expression of both sifA and sifB, which are important for Salmonella filaments formation within host. Treatment of Salmonella with sub-MIC of ciprofloxacin reduced bacterial capacity to kill mice infection models. A lower mortality rate was observed in mice injected with Salmonella treated with sub-MIC of ciprofloxacin as compared to mice inoculated with untreated bacteria. Collectively, current findings indicate that, in addition to its bactericidal potential, sub-MIC of ciprofloxacin could inhibit Salmonella intracellular survival, virulence genes expression as well as host pathogenesis, providing another mechanism for ciprofloxacin in limiting Salmonella host infection.

[1]  T. Dallman,et al.  Emergence of phylogenetically diverse and fluoroquinolone resistant Salmonella Enteritidis as a cause of invasive nontyphoidal Salmonella disease in Ghana , 2019, PLoS neglected tropical diseases.

[2]  L. J. Mota,et al.  SsaV Interacts with SsaL to Control the Translocon-to-Effector Switch in the Salmonella SPI-2 Type Three Secretion System , 2018, mBio.

[3]  Nora C. Toussaint,et al.  Genomic and Geographic Context for the Evolution of High-Risk Carbapenem-Resistant Enterobacter cloacae Complex Clones ST171 and ST78 , 2018, mBio.

[4]  A. Aseffa,et al.  Molecular epidemiology of fluoroquinolone resistant Salmonella in Africa: A systematic review and meta-analysis , 2018, PloS one.

[5]  Hong-Xia Jiang,et al.  Resistance mechanisms and fitness of Salmonella Typhimurium and Salmonella Enteritidis mutants evolved under selection with ciprofloxacin in vitro , 2017, Scientific Reports.

[6]  B. Finlay,et al.  What the SIF Is Happening—The Role of Intracellular Salmonella-Induced Filaments , 2017, Front. Cell. Infect. Microbiol..

[7]  J. Capelo,et al.  Comparative subproteomic analysis of clinically acquired fluoroquinolone resistance and ciprofloxacin stress in Salmonella Typhimurium DT104B , 2017, Proteomics. Clinical applications.

[8]  L. Good,et al.  Targeting the hard to reach: challenges and novel strategies in the treatment of intracellular bacterial infections , 2017, British journal of pharmacology.

[9]  X. Jiao,et al.  Influence of Salmonella enterica serovar Pullorum pathogenicity island 2 on type III secretion system effector gene expression in chicken macrophage HD11 cells , 2017, Avian pathology : journal of the W.V.P.A.

[10]  C. MacLennan,et al.  A Systematic Review of the Incidence, Risk Factors and Case Fatality Rates of Invasive Nontyphoidal Salmonella (iNTS) Disease in Africa (1966 to 2014) , 2017, PLoS neglected tropical diseases.

[11]  S. Kim,et al.  Analysis of the Fluoroquinolone Antibiotic Resistance Mechanism of Salmonella enterica Isolates. , 2016, Journal of microbiology and biotechnology.

[12]  I. Contreras,et al.  Exposure to sub-inhibitory concentrations of cefotaxime enhances the systemic colonization of Salmonella Typhimurium in BALB/c mice , 2015, Open Biology.

[13]  Christopher M. Parry,et al.  Antimicrobial Resistance , and Antimicrobial Management of Invasive Salmonella Infections , 2015 .

[14]  J. Turnidge,et al.  Susceptibility Test Methods: Dilution and Disk Diffusion Methods* , 2015 .

[15]  A. Berndt,et al.  Immune Reaction and Survivability of Salmonella Typhimurium and Salmonella Infantis after Infection of Primary Avian Macrophages , 2015, PloS one.

[16]  Youngjoo Byun,et al.  6-Gingerol reduces Pseudomonas aeruginosa biofilm formation and virulence via quorum sensing inhibition , 2015, Scientific Reports.

[17]  Christopher C. Overall,et al.  Analysis of the Salmonella regulatory network suggests involvement of SsrB and H-NS in σE-regulated SPI-2 gene expression , 2015, Front. Microbiol..

[18]  Daofeng Liu,et al.  Effective cancer vaccine platform based on attenuated salmonella and a type III secretion system. , 2014, Cancer research.

[19]  Diarmaid Hughes,et al.  Microbiological effects of sublethal levels of antibiotics , 2014, Nature Reviews Microbiology.

[20]  M. Maksoud,et al.  Multi-drug resistance and reduced susceptibility to ciprofloxacin among Salmonella enterica serovar Typhi isolates from the Middle East and Central Asia , 2014, New microbes and new infections.

[21]  J. Fierer,et al.  Diarrhea and Colitis in Mice Require the Salmonella Pathogenicity Island 2-Encoded Secretion Function but Not SifA or Spv Effectors , 2012, Infection and Immunity.

[22]  R. Black,et al.  Typhoid fever and paratyphoid fever: Systematic review to estimate global morbidity and mortality for 2010 , 2012, Journal of global health.

[23]  M. Hensel,et al.  Divergent Roles of Salmonella Pathogenicity Island 2 and Metabolic Traits during Interaction of S. enterica Serovar Typhimurium with Host Cells , 2012, PloS one.

[24]  M. Hensel,et al.  Evaluation of Salmonella enterica Type III Secretion System Effector Proteins as Carriers for Heterologous Vaccine Antigens , 2012, Infection and Immunity.

[25]  M. Hensel,et al.  Salmonella enterica as a vaccine carrier. , 2012, Future microbiology.

[26]  G. Menezes,et al.  Antimicrobial resistance in typhoidal salmonellae. , 2011, Indian journal of medical microbiology.

[27]  J. Vila,et al.  Repression of Invasion Genes and Decreased Invasion in a High-Level Fluoroquinolone-Resistant Salmonella Typhimurium Mutant , 2009, PloS one.

[28]  M. Hensel,et al.  Systematic Analysis of the SsrAB Virulon of Salmonella enterica , 2009, Infection and Immunity.

[29]  H. Lillehoj,et al.  Induction of CXC Chemokine Messenger-RNA Expression in Chicken Oviduct Epithelial Cells by Salmonella enterica Serovar Enteritidis via the Type Three Secretion System–1 , 2009, Avian diseases.

[30]  H. Lillehoj,et al.  Functions exerted by the virulence-associated type-three secretion systems during Salmonella enterica serovar Enteritidis invasion into and survival within chicken oviduct epithelial cells and macrophages , 2009, Avian pathology : journal of the W.V.P.A.

[31]  J. Pagés,et al.  Multiple Regulatory Pathways Associated with High-Level Ciprofloxacin and Multidrug Resistance in Salmonella enterica Serovar Enteritidis: Involvement of ramA and Other Global Regulators , 2008, Antimicrobial Agents and Chemotherapy.

[32]  J. Fierer,et al.  Identification of Salmonella SPI-2 secretion system components required for SpvB-mediated cytotoxicity in macrophages and virulence in mice. , 2008, FEMS immunology and medical microbiology.

[33]  M. Hensel,et al.  Salmonella pathogenicity islands in host specificity, host pathogen-interactions and antibiotics resistance of Salmonella enterica. , 2007, Berliner und Munchener tierarztliche Wochenschrift.

[34]  F. Baquero,et al.  Antibiotics as intermicrobial signaling agents instead of weapons , 2006, Proceedings of the National Academy of Sciences.

[35]  G. Cornelis,et al.  The type III secretion injectisome , 2006, Nature Reviews Microbiology.

[36]  J. Galán,et al.  Manipulation of the host actin cytoskeleton by Salmonella--all in the name of entry. , 2005, Current opinion in microbiology.

[37]  M. Hensel,et al.  Cellular microbiology of intracellular Salmonella enterica: functions of the type III secretion system encoded by Salmonella pathogenicity island 2 , 2004, Cellular and Molecular Life Sciences CMLS.

[38]  J. Rotschafer,et al.  Application of fluoroquinolone pharmacodynamics. , 2000, The Journal of antimicrobial chemotherapy.

[39]  Sezgin Erdoğan,et al.  Environmental regulation of Salmonella pathogenicity island 2 gene expression , 1999, Molecular microbiology.

[40]  S. Falkow,et al.  Functional analysis of ssaJ and the ssaK/U operon, 13 genes encoding components of the type III secretion apparatus of Salmonella Pathogenicity Island 2 , 1997, Molecular microbiology.

[41]  T. Whittam,et al.  Molecular genetic relationships of the salmonellae , 1996, Applied and environmental microbiology.

[42]  J. Pocidalo Use of fluoroquinolones for intracellular pathogens. , 1989, Reviews of infectious diseases.

[43]  J. Crane,et al.  Effect of ciprofloxacin on intracellular organisms: in-vitro and in-vivo studies. , 1986, The Journal of antimicrobial chemotherapy.