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. 2018 Apr 5;9:649. doi: 10.3389/fmicb.2018.00649

FIGURE 8.

FIGURE 8

Model of the binding of MAB_4384 to its operator and regulation of the MmpS5/MmpL5 efflux pump machinery. In the absence of drug, two MAB_4384 dimers bind to their DNA operator located in the intergenic region (IRS5/L5) between the divergently transcribed MAB_4384 (encoding the TetR regulator) and MAB_4383c/MAB_4382c (encoding the MmpS5/MmpL5 efflux pump) (1). This action represses the transcription of MAB_4384 (2), MAB_4383c (3) and MAB_4382c (4), predisposing the bacteria to drug susceptibility. When the TAC derivatives bind to MAB_4384 (5) or if MAB_4384 harbors the D14N or F57L mutations (6), the regulator loses affinity for the operator, leading to derepression of MAB_4384 itself (7), MAB_4383c (8) and MAB_4382c (9). This triggers high levels of expression of the MmpS5/MmpL5 complex in the plasma membrane and the subsequent export of the TAC analogs outside the bacteria (10), reducing susceptibility to the compounds.