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Regulation of multidrug resistance in Lactococcus lactis

(2009) Agustiandari, Herfita

The multidrug resistance (MDR) phenomenon is the ability of cells to develop resistance against a wide range of structurally unrelated toxic molecules. MDR is caused by the (over) expression of transporters that expel these compounds from the cell. Multidrug resistance has lead to multiple complications in the treatment of for instance cancer or infectious diseases. The introduction and improper use of antibiotics have led to a selection of bacteria that by mutation(s) in their genome developed resistance mechanisms which allowed them to survive under this severe antibiotics pressure. Sequence analysis conducted on several bacterial genomes revealed that the presence of MDR-like transporters is ubiquitous in nature. The majority of bacterial MDR transporters are subject to regulation at the transcriptional level by local or global regulatory proteins. In general, bacteria harbor resistance mechanisms which allow them to respond to the exposure to toxic molecules in the environment. This condition resulted in the up-regulation of low-expressed MDR transporters in the cells. A typical MDR regulator comprises of two domains; the N-terminal DNA binding domain and the C-terminal ligand binding domain. A common feature of the DNA binding domain is the presence of the helix-turn-helix (HTH) motif. Further classification of MDR regulators is based on their high sequence homology of the DNA binding domain, and on the basis of this feature four different families can be assigned: AraC, MarR, MerR, and TetR. Interestingly, recent findings indicate that the MDR regulator LmrR of Lactococcus lactis that belongs to the PadR family of transcriptional regulators have not been implicated in MDR. However, our findings show that LmrR function as the transcriptional regulator for the major MDR transporter LmrCD in Lactococcus lactis. Unlike the membrane bound MDR transporters, transcriptional regulators are soluble proteins and can be overexpressed relatively straight forward to a higher amount. A structural and functional characterization of these MDR transcriptional regulators is therefore important because these proteins often recognize a similar range of substrates as observed for the transporter that they regulate. This feature makes transcriptional regulators as ideal candidates to study the molecular basis of multidrug recognition. These new insights will be useful for the further development of the new antimicrobial compounds.

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