Evolutionary Origins and Functions of RND Efflux Pumps in Bacteria
There are essentially three ways to deal with harmful substances. The most common method is to destroy toxic molecules by breaking them down. An example of this is the use of beta-lactamases, a class of enzymes that break open the β-lactam rings of penicillins, rendering them inactive. Alternatively, an organism can evolve resistance by modifying the target of the toxin. When a given antibiotic binds to a particular site in an enzyme, new mutants with modified binding sites can appear, reducing the antibiotic’s toxicity.
The third strategy is to actively remove the harmful substance from the space where it can cause harm. Bacteria achieve this by using efflux pumps, protein complexes that expel toxins from inside the cell to the environment. Among the several families of efflux pumps, our interest focuses on the Resistance-Nodulation-Division (RND) family. These large protein complexes connect the inner and outer membranes of the bacterial cell, providing an exit path for toxins, antibiotics, superfluous metabolites, and metal ions.
Interestingly, most bacteria appear to possess more RND efflux pumps than they seemingly need. For instance, the most commonly studied bacterium, Escherichia coli, contains five efflux pump systems with virtually overlapping functions. Deletion of any single system does not seem to have any effect, and only when all five systems are deleted simultaneously do the bacteria suffer from the lack of efflux capability. (An exception to this is the existence of RND efflux pumps that specifically export metal ions, such as the CusCFBA system of E. coli.)
In this project, we set out to investigate the evolutionary origins of one of the efflux pumps, namely the MdtABC system. Mdt stands for multidrug transport, a rather generic name reflecting the broad range of substances transported by this protein assembly. While the vast majority of RND efflux pumps are composed of one inner membrane component, the MdtABC system contains two, MdtB and MdtC. Why?
In our article, Phylogenetic analysis reveals an ancient gene duplication as the origin of the MdtABC efflux pump, we deduced the evolutionary history of this assembly. We showed that, contrary to common belief, the inner membrane component was duplicated only once, early in the evolution of bacteria, and the overall architecture of the complex has remained relatively stable over billions of years. This finding suggests that the MdtABC system has a specific and unique role in bacterial metabolism, which cannot be effectively replaced by other efflux pumps. Otherwise, the MdtABC system would have been lost as redundant.
What role does the MdtABC system play? That remains to be uncovered.
Publications:
- K. Górecki & M.M. McEvoy, Phylogenetic analysis reveals an ancient gene duplication as the origin of the MdtABC efflux pump, (2020), PLOS ONE 15(2): e0228877. Read