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Host-dependent Induction of Transient Antibiotic Resistance: A Prelude to Treatment Failure.

Kubicek-Sutherland JZ, Heithoff DM, Ersoy SC, Shimp WR, House JK, Marth JD, Smith JW, Mahan MJ - EBioMedicine (2015)

Bottom Line: This mechanism has escaped prior detection because it is reversible and operates within a subset of host tissues and cells.Bacterial pathogens are thereby protected while their survival promotes the emergence of permanent drug resistance.This host-dependent mechanism of transient antibiotic resistance is applicable to multiple pathogens and has implications for the development of more effective antimicrobial therapies.

View Article: PubMed Central - PubMed

Affiliation: Dept. of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, CA 93106, USA.

ABSTRACT
Current antibiotic testing does not include the potential influence of host cell environment on microbial susceptibility and antibiotic resistance, hindering appropriate therapeutic intervention. We devised a strategy to identify the presence of host-pathogen interactions that alter antibiotic efficacy in vivo. Our findings revealed a bacterial mechanism that promotes antibiotic resistance in vivo at concentrations of drug that far exceed dosages determined by standardized antimicrobial testing. This mechanism has escaped prior detection because it is reversible and operates within a subset of host tissues and cells. Bacterial pathogens are thereby protected while their survival promotes the emergence of permanent drug resistance. This host-dependent mechanism of transient antibiotic resistance is applicable to multiple pathogens and has implications for the development of more effective antimicrobial therapies.

No MeSH data available.


Related in: MedlinePlus

Salmonella exhibit high-level antibiotic resistance within cultured macrophages and are refractory to killing by antibiotic treatment. (A) Antimicrobial susceptibility of TIVAR + S. Typhimurium 14028 and TIVAR − S. Typhimurium var. 5 (04)-9639 derived from cultured RAW264.7 murine macrophages was evaluated via MIC determination on LPM pH 5.5 medium containing polymyxin B (PMB) or nalidixic acid (NAL). MIC values were the result of 2 to 3 independent determinations performed in triplicate. (B) Efficacy of antibiotic administration on the proliferation of TIVAR + and TIVAR − Salmonella within cultured RAW264.7 murine macrophages (PMB, gentamicin [GNT]). Values given are the average intracellular CFU ± SEM derived from 2 to 4 independent determinations performed in triplicate. Log transformed intracellular CFU data were analyzed for statistical significance using ANOVA; *P < 0.05, ***P < 0.001.
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f0025: Salmonella exhibit high-level antibiotic resistance within cultured macrophages and are refractory to killing by antibiotic treatment. (A) Antimicrobial susceptibility of TIVAR + S. Typhimurium 14028 and TIVAR − S. Typhimurium var. 5 (04)-9639 derived from cultured RAW264.7 murine macrophages was evaluated via MIC determination on LPM pH 5.5 medium containing polymyxin B (PMB) or nalidixic acid (NAL). MIC values were the result of 2 to 3 independent determinations performed in triplicate. (B) Efficacy of antibiotic administration on the proliferation of TIVAR + and TIVAR − Salmonella within cultured RAW264.7 murine macrophages (PMB, gentamicin [GNT]). Values given are the average intracellular CFU ± SEM derived from 2 to 4 independent determinations performed in triplicate. Log transformed intracellular CFU data were analyzed for statistical significance using ANOVA; *P < 0.05, ***P < 0.001.

Mentions: The degree of antibiotic resistance as a function of growth within cultured macrophages was evaluated using TIVAR + and TIVAR − bacteria that have comparable virulence in a murine model of typhoid fever (Heithoff et al., 2012). TIVAR + Salmonella derived from infected cultured macrophages exhibited high-level PMB resistance via MIC determination in vitro, whereas TIVAR − Salmonella did not (Fig. 4A). Further, PMB treatment of infected cultured macrophages showed that internalized TIVAR + bacteria were much more resistant to PMB than TIVAR − bacteria (P < 0.001; Fig. 4B) (the inability of PMB to clear TIVAR − bacteria is presumably due to relatively low intracellular activity of cationic antimicrobial peptides (Buyck et al., 2013; Carryn et al., 2003)). These findings indicate that internalized TIVAR + bacteria are refractory to killing by PMB relative to bacteria that do not exhibit the TIVAR phenotype.


Host-dependent Induction of Transient Antibiotic Resistance: A Prelude to Treatment Failure.

Kubicek-Sutherland JZ, Heithoff DM, Ersoy SC, Shimp WR, House JK, Marth JD, Smith JW, Mahan MJ - EBioMedicine (2015)

Salmonella exhibit high-level antibiotic resistance within cultured macrophages and are refractory to killing by antibiotic treatment. (A) Antimicrobial susceptibility of TIVAR + S. Typhimurium 14028 and TIVAR − S. Typhimurium var. 5 (04)-9639 derived from cultured RAW264.7 murine macrophages was evaluated via MIC determination on LPM pH 5.5 medium containing polymyxin B (PMB) or nalidixic acid (NAL). MIC values were the result of 2 to 3 independent determinations performed in triplicate. (B) Efficacy of antibiotic administration on the proliferation of TIVAR + and TIVAR − Salmonella within cultured RAW264.7 murine macrophages (PMB, gentamicin [GNT]). Values given are the average intracellular CFU ± SEM derived from 2 to 4 independent determinations performed in triplicate. Log transformed intracellular CFU data were analyzed for statistical significance using ANOVA; *P < 0.05, ***P < 0.001.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4588393&req=5

f0025: Salmonella exhibit high-level antibiotic resistance within cultured macrophages and are refractory to killing by antibiotic treatment. (A) Antimicrobial susceptibility of TIVAR + S. Typhimurium 14028 and TIVAR − S. Typhimurium var. 5 (04)-9639 derived from cultured RAW264.7 murine macrophages was evaluated via MIC determination on LPM pH 5.5 medium containing polymyxin B (PMB) or nalidixic acid (NAL). MIC values were the result of 2 to 3 independent determinations performed in triplicate. (B) Efficacy of antibiotic administration on the proliferation of TIVAR + and TIVAR − Salmonella within cultured RAW264.7 murine macrophages (PMB, gentamicin [GNT]). Values given are the average intracellular CFU ± SEM derived from 2 to 4 independent determinations performed in triplicate. Log transformed intracellular CFU data were analyzed for statistical significance using ANOVA; *P < 0.05, ***P < 0.001.
Mentions: The degree of antibiotic resistance as a function of growth within cultured macrophages was evaluated using TIVAR + and TIVAR − bacteria that have comparable virulence in a murine model of typhoid fever (Heithoff et al., 2012). TIVAR + Salmonella derived from infected cultured macrophages exhibited high-level PMB resistance via MIC determination in vitro, whereas TIVAR − Salmonella did not (Fig. 4A). Further, PMB treatment of infected cultured macrophages showed that internalized TIVAR + bacteria were much more resistant to PMB than TIVAR − bacteria (P < 0.001; Fig. 4B) (the inability of PMB to clear TIVAR − bacteria is presumably due to relatively low intracellular activity of cationic antimicrobial peptides (Buyck et al., 2013; Carryn et al., 2003)). These findings indicate that internalized TIVAR + bacteria are refractory to killing by PMB relative to bacteria that do not exhibit the TIVAR phenotype.

Bottom Line: This mechanism has escaped prior detection because it is reversible and operates within a subset of host tissues and cells.Bacterial pathogens are thereby protected while their survival promotes the emergence of permanent drug resistance.This host-dependent mechanism of transient antibiotic resistance is applicable to multiple pathogens and has implications for the development of more effective antimicrobial therapies.

View Article: PubMed Central - PubMed

Affiliation: Dept. of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, CA 93106, USA.

ABSTRACT
Current antibiotic testing does not include the potential influence of host cell environment on microbial susceptibility and antibiotic resistance, hindering appropriate therapeutic intervention. We devised a strategy to identify the presence of host-pathogen interactions that alter antibiotic efficacy in vivo. Our findings revealed a bacterial mechanism that promotes antibiotic resistance in vivo at concentrations of drug that far exceed dosages determined by standardized antimicrobial testing. This mechanism has escaped prior detection because it is reversible and operates within a subset of host tissues and cells. Bacterial pathogens are thereby protected while their survival promotes the emergence of permanent drug resistance. This host-dependent mechanism of transient antibiotic resistance is applicable to multiple pathogens and has implications for the development of more effective antimicrobial therapies.

No MeSH data available.


Related in: MedlinePlus