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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 and Yersinia exhibit high-level antibiotic resistance under conditions that simulate host microenvironments. (A) S. Typhimurium 14028 was grown in either the Mueller–Hinton Broth (MHB) (Clinical and Laboratory Standards Institute, 2012) or low phosphate, low magnesium medium (LPM) (Coombes et al., 2004) at the pH indicated, and the minimum inhibitory concentration (MIC) of a panel of antibiotics was determined in the same medium (Clinical and Laboratory Standards Institute, 2012; Wiegand et al., 2008). The effect of growth conditions on antibiotic resistance was calculated by comparing the MIC in LPM medium divided by the MIC in MHB medium at both pH 5.5 and pH 7 (unbuffered) (ratio of LPM pH 5.5/pH 7.0 to MHB pH 5.5/pH 7.2). Drugs: polymyxin B, PMB; colistin sulfate, CST; trimethoprim, TMP; sulfamethoxazole, SMX; kanamycin, KAN; neomycin, NEO; streptomycin, STR; tetracycline, TCN; chloramphenicol, CAM; florfenicol, FFC; ampicillin, AMP; ceftriaxone, CTX; ceftiofur, CEF; nalidixic acid, NAL; ciprofloxacin, CIP; enrofloxacin, EFX. (B) The degree of Y. pseudotuberculosis IP32953 susceptibility to antibiotics as a function of growth conditions. MIC values were obtained from at least 3 independent determinations.
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f0010: Salmonella and Yersinia exhibit high-level antibiotic resistance under conditions that simulate host microenvironments. (A) S. Typhimurium 14028 was grown in either the Mueller–Hinton Broth (MHB) (Clinical and Laboratory Standards Institute, 2012) or low phosphate, low magnesium medium (LPM) (Coombes et al., 2004) at the pH indicated, and the minimum inhibitory concentration (MIC) of a panel of antibiotics was determined in the same medium (Clinical and Laboratory Standards Institute, 2012; Wiegand et al., 2008). The effect of growth conditions on antibiotic resistance was calculated by comparing the MIC in LPM medium divided by the MIC in MHB medium at both pH 5.5 and pH 7 (unbuffered) (ratio of LPM pH 5.5/pH 7.0 to MHB pH 5.5/pH 7.2). Drugs: polymyxin B, PMB; colistin sulfate, CST; trimethoprim, TMP; sulfamethoxazole, SMX; kanamycin, KAN; neomycin, NEO; streptomycin, STR; tetracycline, TCN; chloramphenicol, CAM; florfenicol, FFC; ampicillin, AMP; ceftriaxone, CTX; ceftiofur, CEF; nalidixic acid, NAL; ciprofloxacin, CIP; enrofloxacin, EFX. (B) The degree of Y. pseudotuberculosis IP32953 susceptibility to antibiotics as a function of growth conditions. MIC values were obtained from at least 3 independent determinations.

Mentions: Growth of S. enterica Typhimurium in LPM pH 5.5 medium was linked to high-level resistance to polymyxin B (PMB; 64-fold) and colistin (CST; 256-fold), cationic peptides that disrupt Gram-negative membranes (Bergen et al., 2012; Landman et al., 2008) (Fig. 1A). We also observed a mild resistance to trimethoprim (TMP; 4-fold), an inhibitor of folate metabolism (Burchall, 1973). Under these conditions, Salmonella remains viable, and continues to grow at antibiotic concentrations that far exceed those achieved in treating human infections (0.5 to 2.5 mg/l) (Michalopoulos and Falagas, 2011; National Institutes of Health, 2014b; Sandri et al., 2013; Zavascki et al., 2008). Some other antibiotics examined were subject to pH and/or media composition effects on drug efficacy including kanamycin, streptomycin, and ciprofloxacin. In those cases, we could not determine the induction of antibiotic resistance. In other cases the efficacy of antibiotics was altogether unaffected, including tetracycline, chloramphenicol, and ceftiofur. Many pathogenic Salmonella serovars (serotypic variants) derived from human and livestock infections (Heithoff et al., 2008) exhibited high-level resistance to antibiotics PMB, CST and TMP when grown in LPM pH 5.5 medium: S. Typhimurium (5/6), S. Enteritidis (1/1), S. Dublin (2/2), S. Newport (1/2), S. Bovismorbificans (1/2), and Salmonella C1 K00-670 (1/1) (Supplementary Table 1). These data indicate that induction of antibiotic resistance under conditions simulating the phagosome is not a strain-specific phenomenon.


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 and Yersinia exhibit high-level antibiotic resistance under conditions that simulate host microenvironments. (A) S. Typhimurium 14028 was grown in either the Mueller–Hinton Broth (MHB) (Clinical and Laboratory Standards Institute, 2012) or low phosphate, low magnesium medium (LPM) (Coombes et al., 2004) at the pH indicated, and the minimum inhibitory concentration (MIC) of a panel of antibiotics was determined in the same medium (Clinical and Laboratory Standards Institute, 2012; Wiegand et al., 2008). The effect of growth conditions on antibiotic resistance was calculated by comparing the MIC in LPM medium divided by the MIC in MHB medium at both pH 5.5 and pH 7 (unbuffered) (ratio of LPM pH 5.5/pH 7.0 to MHB pH 5.5/pH 7.2). Drugs: polymyxin B, PMB; colistin sulfate, CST; trimethoprim, TMP; sulfamethoxazole, SMX; kanamycin, KAN; neomycin, NEO; streptomycin, STR; tetracycline, TCN; chloramphenicol, CAM; florfenicol, FFC; ampicillin, AMP; ceftriaxone, CTX; ceftiofur, CEF; nalidixic acid, NAL; ciprofloxacin, CIP; enrofloxacin, EFX. (B) The degree of Y. pseudotuberculosis IP32953 susceptibility to antibiotics as a function of growth conditions. MIC values were obtained from at least 3 independent determinations.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

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

f0010: Salmonella and Yersinia exhibit high-level antibiotic resistance under conditions that simulate host microenvironments. (A) S. Typhimurium 14028 was grown in either the Mueller–Hinton Broth (MHB) (Clinical and Laboratory Standards Institute, 2012) or low phosphate, low magnesium medium (LPM) (Coombes et al., 2004) at the pH indicated, and the minimum inhibitory concentration (MIC) of a panel of antibiotics was determined in the same medium (Clinical and Laboratory Standards Institute, 2012; Wiegand et al., 2008). The effect of growth conditions on antibiotic resistance was calculated by comparing the MIC in LPM medium divided by the MIC in MHB medium at both pH 5.5 and pH 7 (unbuffered) (ratio of LPM pH 5.5/pH 7.0 to MHB pH 5.5/pH 7.2). Drugs: polymyxin B, PMB; colistin sulfate, CST; trimethoprim, TMP; sulfamethoxazole, SMX; kanamycin, KAN; neomycin, NEO; streptomycin, STR; tetracycline, TCN; chloramphenicol, CAM; florfenicol, FFC; ampicillin, AMP; ceftriaxone, CTX; ceftiofur, CEF; nalidixic acid, NAL; ciprofloxacin, CIP; enrofloxacin, EFX. (B) The degree of Y. pseudotuberculosis IP32953 susceptibility to antibiotics as a function of growth conditions. MIC values were obtained from at least 3 independent determinations.
Mentions: Growth of S. enterica Typhimurium in LPM pH 5.5 medium was linked to high-level resistance to polymyxin B (PMB; 64-fold) and colistin (CST; 256-fold), cationic peptides that disrupt Gram-negative membranes (Bergen et al., 2012; Landman et al., 2008) (Fig. 1A). We also observed a mild resistance to trimethoprim (TMP; 4-fold), an inhibitor of folate metabolism (Burchall, 1973). Under these conditions, Salmonella remains viable, and continues to grow at antibiotic concentrations that far exceed those achieved in treating human infections (0.5 to 2.5 mg/l) (Michalopoulos and Falagas, 2011; National Institutes of Health, 2014b; Sandri et al., 2013; Zavascki et al., 2008). Some other antibiotics examined were subject to pH and/or media composition effects on drug efficacy including kanamycin, streptomycin, and ciprofloxacin. In those cases, we could not determine the induction of antibiotic resistance. In other cases the efficacy of antibiotics was altogether unaffected, including tetracycline, chloramphenicol, and ceftiofur. Many pathogenic Salmonella serovars (serotypic variants) derived from human and livestock infections (Heithoff et al., 2008) exhibited high-level resistance to antibiotics PMB, CST and TMP when grown in LPM pH 5.5 medium: S. Typhimurium (5/6), S. Enteritidis (1/1), S. Dublin (2/2), S. Newport (1/2), S. Bovismorbificans (1/2), and Salmonella C1 K00-670 (1/1) (Supplementary Table 1). These data indicate that induction of antibiotic resistance under conditions simulating the phagosome is not a strain-specific phenomenon.

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