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The inoculum effect and band-pass bacterial response to periodic antibiotic treatment.

Tan C, Smith RP, Srimani JK, Riccione KA, Prasada S, Kuehn M, You L - Mol. Syst. Biol. (2012)

Bottom Line: The inoculum effect (IE) refers to the decreasing efficacy of an antibiotic with increasing bacterial density.A critical requirement for this bistability is sufficiently fast degradation of ribosomes, which can result from antibiotic-induced heat-shock response.Our proposed mechanism for the IE may be generally applicable to other bacterial species treated with antibiotics targeting the ribosomes.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Engineering, Duke University, Durham, NC, USA.

ABSTRACT
The inoculum effect (IE) refers to the decreasing efficacy of an antibiotic with increasing bacterial density. It represents a unique strategy of antibiotic tolerance and it can complicate design of effective antibiotic treatment of bacterial infections. To gain insight into this phenomenon, we have analyzed responses of a lab strain of Escherichia coli to antibiotics that target the ribosome. We show that the IE can be explained by bistable inhibition of bacterial growth. A critical requirement for this bistability is sufficiently fast degradation of ribosomes, which can result from antibiotic-induced heat-shock response. Furthermore, antibiotics that elicit the IE can lead to 'band-pass' response of bacterial growth to periodic antibiotic treatment: the treatment efficacy drastically diminishes at intermediate frequencies of treatment. Our proposed mechanism for the IE may be generally applicable to other bacterial species treated with antibiotics targeting the ribosomes.

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Related in: MedlinePlus

Kanamycin, but not chloramphenicol, led to IE in enterotoxigenic E. coli (ETEC) and S. typhimurium. (A) ETEC exhibited the inoculum effect at 13–17.5 μg/ml kanamycin. Red and black lines represent high and low initial cell density, respectively. Dark gray regions indicate that populations exhibited IE. Light gray regions indicate that both populations went extinct. (B) ETEC did not exhibit inoculum effect at all tested concentrations of chloramphenicol. (C) S. typhimurium exhibited the inoculum effect at 20–60 μg/ml kanamycin. (D) S. typhimurium did not exhibit inoculum effect at all tested concentrations of chloramphenicol. See additional results in Supplementary Figure S3. Source data is available for this figure in the Supplementary Information.
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f3: Kanamycin, but not chloramphenicol, led to IE in enterotoxigenic E. coli (ETEC) and S. typhimurium. (A) ETEC exhibited the inoculum effect at 13–17.5 μg/ml kanamycin. Red and black lines represent high and low initial cell density, respectively. Dark gray regions indicate that populations exhibited IE. Light gray regions indicate that both populations went extinct. (B) ETEC did not exhibit inoculum effect at all tested concentrations of chloramphenicol. (C) S. typhimurium exhibited the inoculum effect at 20–60 μg/ml kanamycin. (D) S. typhimurium did not exhibit inoculum effect at all tested concentrations of chloramphenicol. See additional results in Supplementary Figure S3. Source data is available for this figure in the Supplementary Information.

Mentions: To examine generality of IE in bacterial pathogens, we tested enterotoxigenic E. coli (ATCC 43886, Supplementary Methods) and Salmonella typhimurium (ATCC 14028, Supplementary Methods). These pathogens also exhibited IE when treated with kanamycin, but not with chloramphenicol (Figure 3A–D; Supplementary Figure S3A–D). In support of the notion that HSR underlies IE, treatment with kanamycin, but not with chloramphenicol, resulted in HSR in both of these pathogens (Supplementary Figure S3E).


The inoculum effect and band-pass bacterial response to periodic antibiotic treatment.

Tan C, Smith RP, Srimani JK, Riccione KA, Prasada S, Kuehn M, You L - Mol. Syst. Biol. (2012)

Kanamycin, but not chloramphenicol, led to IE in enterotoxigenic E. coli (ETEC) and S. typhimurium. (A) ETEC exhibited the inoculum effect at 13–17.5 μg/ml kanamycin. Red and black lines represent high and low initial cell density, respectively. Dark gray regions indicate that populations exhibited IE. Light gray regions indicate that both populations went extinct. (B) ETEC did not exhibit inoculum effect at all tested concentrations of chloramphenicol. (C) S. typhimurium exhibited the inoculum effect at 20–60 μg/ml kanamycin. (D) S. typhimurium did not exhibit inoculum effect at all tested concentrations of chloramphenicol. See additional results in Supplementary Figure S3. Source data is available for this figure in the Supplementary Information.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3472685&req=5

f3: Kanamycin, but not chloramphenicol, led to IE in enterotoxigenic E. coli (ETEC) and S. typhimurium. (A) ETEC exhibited the inoculum effect at 13–17.5 μg/ml kanamycin. Red and black lines represent high and low initial cell density, respectively. Dark gray regions indicate that populations exhibited IE. Light gray regions indicate that both populations went extinct. (B) ETEC did not exhibit inoculum effect at all tested concentrations of chloramphenicol. (C) S. typhimurium exhibited the inoculum effect at 20–60 μg/ml kanamycin. (D) S. typhimurium did not exhibit inoculum effect at all tested concentrations of chloramphenicol. See additional results in Supplementary Figure S3. Source data is available for this figure in the Supplementary Information.
Mentions: To examine generality of IE in bacterial pathogens, we tested enterotoxigenic E. coli (ATCC 43886, Supplementary Methods) and Salmonella typhimurium (ATCC 14028, Supplementary Methods). These pathogens also exhibited IE when treated with kanamycin, but not with chloramphenicol (Figure 3A–D; Supplementary Figure S3A–D). In support of the notion that HSR underlies IE, treatment with kanamycin, but not with chloramphenicol, resulted in HSR in both of these pathogens (Supplementary Figure S3E).

Bottom Line: The inoculum effect (IE) refers to the decreasing efficacy of an antibiotic with increasing bacterial density.A critical requirement for this bistability is sufficiently fast degradation of ribosomes, which can result from antibiotic-induced heat-shock response.Our proposed mechanism for the IE may be generally applicable to other bacterial species treated with antibiotics targeting the ribosomes.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Engineering, Duke University, Durham, NC, USA.

ABSTRACT
The inoculum effect (IE) refers to the decreasing efficacy of an antibiotic with increasing bacterial density. It represents a unique strategy of antibiotic tolerance and it can complicate design of effective antibiotic treatment of bacterial infections. To gain insight into this phenomenon, we have analyzed responses of a lab strain of Escherichia coli to antibiotics that target the ribosome. We show that the IE can be explained by bistable inhibition of bacterial growth. A critical requirement for this bistability is sufficiently fast degradation of ribosomes, which can result from antibiotic-induced heat-shock response. Furthermore, antibiotics that elicit the IE can lead to 'band-pass' response of bacterial growth to periodic antibiotic treatment: the treatment efficacy drastically diminishes at intermediate frequencies of treatment. Our proposed mechanism for the IE may be generally applicable to other bacterial species treated with antibiotics targeting the ribosomes.

Show MeSH
Related in: MedlinePlus