Towards the search for an improved healthcare, the development of multidrug resistance is a serious challenge. Mostly it develops due to the active pumping of a broad spectrum of cytotoxic molecules out of the cells. Most of these compounds are chemically distinct and may include antimalarials, antibiotics, cancer drugs in humans and herbicides (Higgins, 2007).
ATP-switch model for ABC transporters.Also called the ABC transporters, the ATP-binding cassette is present in all organisms cells. It utilizes the ATP/hydrolysis energy to transport substrates across the cell membranes. Though most of them are specific to a specific ligand such as an amino acid, some of them have evolved a broad specificity especially for the hydrophobic molecules. They have been implicated in cancer drug resistance, antibiotic resistance as well as resistance to fungi and parasitic drugs in animals. In plants, resistance to herbicides is also associated with ABC transporters.
There are no structures of ABC transporters that have been identified with a bound substrate. From other studies therefore, it is generally concluded that drugs bind to a high affinity site(s). This is usually on the protein binding sites located on the lipid bilayer. Just like any other mutations, those mutations that alter the drug binding protein can result in to drug resistance (Higgins, 2007).Comparison of multidrug transporters.
1. Multidrug transporters are enzymes whose functions can be explained using simple kinetic schemes. Substrates usually bind to the high affinity sites that are exposed to one side of the membrane. This results in to some conformational change in the protein that can be within a protein domain or transmitted between the domains.2.
Crossing of the substrate=rates through the bilayer membrane is through a process that shields them from the lipid phase. This has been clearly observed in some cases since most of the multidrug resistant transporters are closely associated too those transporters that do transport hydrophilic substances so as to shield them from the lipid phase. The pathway cannot be regarded to be a channel as it opens in an alternately during the transport cycle rather that simultaneously at both ends.3.
Just like the phospholipid flipases/floppases that generate lipid asymmetry in the membrane, multidrug transporters obtain their substrates from the inner side of the bilayer with an exception only to AcrB. It can probably be thus argued out that capturing of the drugs from just before they enter cytoplasm from the inner side of the bilayer is probably the most effective means of making sure that the drug does not interact with its cytoplasmic target.4. Multispecificity is achieved in the soluble drug binding protein by having a single, large and flexible hydrophobic pocket that eventually shields the drug from the lipid and aqueous phase.
Sometimes, these pockets can either two identical or even different drug molecules at once.ConclusionThe struggle to overcome drug resistance has proved to be unsatisfactory since the effort put in trying to chemically modify drugs so that they are no longer substrates for multidrug transporters has been done ‘blindly’ as there is no structural data on the nature of multidrug-binding sites. Probably thus, understanding the structure of multidrug-binding sites on the transporters can enable the drugs to be modifies so as to avoid resistance.
