Permeability of bacteria to antibacterial agents

Abstract

The passive permeability of bacteria to antibacterial compounds is an important determinant of antibacterial potency. However, understanding the quantitative relationship between permeability and MIC (minimum inhibitory concentration) has been elusive. This chapter reviews what is understood about the permeability of different layers of the bacterial cell envelope. A quantitative definition of non-permeant is provided, and permeability is incorporated into quantitative dynamic models of intracellular concentrations of passively permeating compounds. The effect of outwardly directed (efflux) pumping is analyzed by constructing quantitative whole-cell kinetic models of permeation and efflux and comparing results to experimental data from the literature. A key insight is that permeability and efflux coefficients, for any particular layer of the cell-envelope, appear in all modeling equations in inverse ratio to one another. This means that, paradoxically, permeability in the absence of efflux or reaction for most compounds in drug discovery (i.e., for ones for which the permeability coefficient exceeds about 5 ∈× ∈10-9 cm s-1) is generally not a determinant of the MIC (e.g., in pump-deficient mutants) whereas it is theoretically a determinant in wild strains when efflux is active. Space constraints here prevent the presentation of the derivations of the mechanism-based kinetic modeling equations. However, they have been deposited in full with explanatory text as supplementary material at the Springer-Verlag web site, http:URL. (Nichols 2011).