Tan C, Smith RP, Srimani JK, Riccione KA, Prasada S, Kuehn M, You L.
The inoculum effect and band-pass bacterial response to periodic antibiotic treatment.
Mol. Syst. Biol. 2012; 8: 617
Department of Biomedical Engineering, Duke University, Durham, NC, USA. [more]
The efficacy of many antibiotics decreases with increasing bacterial density, a phenomenon called the ‘inoculum effect’ (IE). This study reveals that, for ribosome-targeting antibiotics, IE is due to bistable inhibition of bacterial growth, which reduces the efficacy of certain treatment frequencies.
Tan C, Phillip Smith R, Srimani JK, Riccione KA, Prasada S, Kuehn M, You L.
Mol Syst Biol. 2012 Oct 9; 8:617
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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kappa represents the concentration of c rliciting half-maximal activation of its positive feedback
reaction_4 (3)
phi
Value: 5.0E-6
Constant
Notes:
phi represents the applied anitbiotic concentration
delta
Value: 1.0E-5
Constant
Notes:
the parameter delta lumps the effects of multiple reactions: it increases with decreasing rates of intrinsic or antibiotic-induced degradation of C (ribosomes), increasing dissociation between the antibiotic and C, and increasing export rate of the antibiotic.
reaction_1
)
