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Multidrug resistance in lactic acid bacteria: molecular mechanisms and clinical relevance
H W van Veen1, A Margolles, M Putman
1Department of Microbiology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Haren, The Netherlands. h.w.van.veen@biol.rug.nl
Abstract:
The active extrusion of cytotoxic compounds from the cell by multidrug transporters is one of the major causes of failure of chemotherapeutic treatment of tumor cells and of infections by pathogenic microorganisms. The secondary multidrug transporter LmrP and the ATP-binding cassette (ABC) type multidrug transporter LmrA in Lactococcus lactis are representatives of the two major classes of multidrug transporters found in pro- and eukaryotic organisms. Therefore, knowledge of the molecular properties of LmrP and LmrA will have a wide significance for multidrug transporters in all living cells, and may enable the development of specific inhibitors and of new drugs which circumvent the action of multidrug transporters. Interestingly, LmrP and LmrA are transport proteins with very different protein structures, which use different mechanisms of energy coupling to transport drugs out of the cell. Surprisingly, both proteins have overlapping specificities for drugs, are inhibited by the same set of modulators, and transport drugs via a similar transport mechanism. The structure-function relationships that dictate drug recognition and transport by LmrP and LmrA will represent an intriguing new area of research.
Insights
Multidrug transporters like LmrP and LmrA expel cytotoxic drugs, causing treatment failure. Studying these transporters may lead to new drugs and inhibitors for cancer and infections.
Area of Science:
- Microbiology
- Biochemistry
- Molecular Biology
Background:
- Multidrug transporters actively expel cytotoxic compounds, leading to treatment failure in cancer and microbial infections.
- Lactococcus lactis possesses two major classes of multidrug transporters: LmrP (secondary transporter) and LmrA (ATP-binding cassette transporter).
- Understanding these transporters is crucial for developing novel therapeutic strategies against drug-resistant diseases.
Purpose of the Study:
- To investigate the molecular properties and structure-function relationships of LmrP and LmrA.
- To compare the drug recognition and transport mechanisms of these two distinct multidrug transporters.
- To identify potential targets for developing specific inhibitors or circumventing drugs.
Main Methods:
- Comparative analysis of LmrP and LmrA structures and energy coupling mechanisms.
- Investigation of substrate specificities and modulator effects on both transporters.
- Elucidation of the transport mechanism employed by LmrP and LmrA.
Main Results:
- LmrP and LmrA, despite differing structures and energy coupling, exhibit overlapping drug specificities.
- Both transporters are inhibited by a common set of modulators.
- Despite structural differences, LmrP and LmrA appear to utilize a similar drug transport mechanism.
Conclusions:
- LmrP and LmrA represent key models for understanding multidrug transport across different life forms.
- Shared drug specificities and modulator effects suggest convergent evolution or conserved functional principles.
- Further research into their structure-function relationships is essential for advancing drug development and overcoming multidrug resistance.