Evolution of Drug resistance to Antimicrobial
The proliferation of drug resistance involves two processes. First, an individual who receives treatment acquires drug resistant infection, and second, drug resistant microbes are transmitted to other individuals, causing new infections that spread drug resistance in the population. At the level of the population, the use of a drug exposes microbes to an environmental stress that selects for drug resistance. This selection pressure can vary in time and space as a result of infection dynamics in the population as well as the number of different drugs used to treat the infected population. In general, the spread of drug resistant infection is determined by the probability that a drug resistant microbe is transmitted to a new host who is then treated with the same drug.
For a single individual, drug resistance is not problematic provided that another drug is available and is effective against the drug resistant microbe. Of course, drug resistance can develop to this drug too. At the level of the population, drug resistance could be avoided or slowed altogether if the use of drugs was stopped or rationed, but at the level of the individual, it is nonsensical to deny necessary treatment. This approach is nonetheless important in regards to the inappropriate use of antimicrobials, which does not jeopardize treatment success and must be averted to decrease overall selection pressure for drug resistance. The sensible use of antimicrobials is crucial to preserving efficacy at the level of the population and also the success of treatment for an individual.
Multi-drug Resistance (MDR) and GST Mechanism
Several cellular mechanisms have been proposed for MDR, namely: extra-cellular drug efflux mediated by P-glycoprotein (P-gp), intracellular entrapment or redistribution of the drug (mediated by multi-drug resistance protein: MRP), drug detoxification (mediated by glutathione S-transferase: GST), altered nuclear target (defects in DNA repair enzymes) and altered apoptotic response (associated with mutated p53 protein).
For example, the mechanism of detoxification of a chemotherapeutic drug by GST involves conjugation of glutathione (GSH) to the electrophilic chemotherapeutic drug, thus removing the potency of the drug. The glutathionylated drug is then broken down further and excreted. For example, cyclophosphamide, a potent alkylating agent used for the treatment of cancer, is activated via oxidation by P450 and converted to mono or di-glutathione derivatives by GST. The resultant glutathione derivatives of cyclophosphamide are not able to alkylate DNA and form inter-strand cross links. The highly reactive DNA-alkylating agent is thus rendered non-toxic to the tumor cells. The glutathionylated cyclophosphamide conjugates can then be pumped out of cells via an ATP-dependent membrane transport protein specific for of GS-conjugates. Alternatively, it can be further converted to derivatives of mercapturic acid, transported into the blood stream, concentrated in the kidney tubule and excreted out of the body.
Targeting the above GST detoxification mechanism, various strategies have been devised to reverse MDR: (1) competitive inhibition of GST, (2) depletion of intracellular GSH, (3) covalent modification of GST. An example of the strategy that aims to inhibit GST is the use of ethacrynic acid in a clinical trial. Another strategy aims to reverse MDR by depleting intracellular GSH using buthionine sulfoximine (BSO), which inhibits glutathione synthase. With less glutathione, less chemotherapeutic drug can be conjugated with glutathione.