Drug efflux pump deficiency and drug target resistance masking in growing bacteria.
Recent experiments have shown that drug efflux pump deficiency not only increases the susceptibility of pathogens to antibiotics, but also seems to "mask" the effects of mutations, that decrease the affinities of drugs to their intracellular targets, on the growth rates of drug-exposed bacteria. That is, in the presence of drugs, the growth rates of drug-exposed WT and target mutated strains are the same in a drug efflux pump deficient background, but the mutants grow faster than WT in a drug efflux pump proficient background. Here, we explain the mechanism of target resistance masking and show that it occurs in response to drug efflux pump inhibition among pathogens with high-affinity drug binding targets, low cell-membrane drug-permeability and insignificant intracellular drug degradation. We demonstrate that target resistance masking is fundamentally linked to growth-bistability, i.e., the existence of 2 different steady state growth rates for one and the same drug concentration in the growth medium. We speculate that target resistance masking provides a hitherto unknown mechanism for slowing down the evolution of target resistance among pathogens.
Department of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden.
David
D
Fange
Karin
K
Nilsson
Tanel
T
Tenson
Måns
M
Ehrenberg
D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics*; D001419:Bacteria / Q000187:drug effects* / Q000254:growth & development; D001692:Biological Transport; D024881:Drug Resistance, Bacterial; D026901:Membrane Transport Proteins / Q000378:metabolism*; D008954:Models, Biological; D008962:Models, Theoretical
D000900:Anti-Bacterial Agents; D026901:Membrane Transport Proteins