Multidrug resistance (MDR) revealed in malignant cell lines was firstly attributed to the activity of multidrug exporters pumping drugs out of the cell. However, mutagenised Escherichia coli develop extraordinary numerous mutants resistant to target inhibitor and we have shown that with mutations mapped around the entire genome most of the mutants were multiple-resistant. In case of one such mutant studied MDR was shown as a sum of individual resistances due to mutations resulted in target and ligand sequestration and induced simultaneously in tightly linked, cassette-like genes. An explanation of local mutagenesis efficiency and the nature of sequestration process is proposed. A cassette-like organization of genes responsible for chemoresistance emergence could promote the local intensity of mutagenesis by a cassette facing the intracellular space and flux and contacting unlike other genes mutagen the first. Target and ligand sequestration could result from clogging the intracellular flux due to cytoplasm geometry alteration attributable to disorder-order transition in natively unfolded proteins affected with mutation.