Resistance in Disease

Background

Resistance is a major problem in both microbial disease and cancer. Treatments that were previously successful against these diseases have been rendered ineffectual by the ability of microbes and cancer cells to rapidly evolve. Understanding and potentially blocking some of the mechanisms through which resistance occurs offers a possibility for the development of novel, effective treatments.

Microbial resistance mechanisms

There are four main ways in which drug resistance in, for example, bacteria may develop. Accumulation of the drugs may be lowered; this may be through reduced permeability of the bacterial membrane to drugs entering the cell, or through the development of membrane pumps which extrude the drugs from the cell.
The target with which the drug interacts may evolve and change conformation, preventing drug binding; if the drug action involves a bacterial metabolic pathway, this pathway may become altered. Finally, mechanisms by which the drug may be deactivated or degraded can develop.

Mechanisms of deactivation/degradation

A topical and important example of this is the resistance of Staphylococcus aureus to penicillin and related compounds. Penicillin functions by destroying bacterial cell walls, exposing the tightly regulated internal environment of the bacteria to the outside world. Resistance S. aureus produces β-lactamases, which are capable of destroying the penicillin molecules, preventing their function. This is the method that MRSA (methicillin resistant Staphylococcus aureus) has developed; MRSA was sensitive to vancomycin and therefore still treatable up until very recently; now there are strains which are resistant even to vancomycin and virtually impossible to treat. S. aureus is a commensal – i.e. it is a normal inhabitant of human skin and mucosal surfaces, such as in the nose – but in the vulnerable, such as those with open wounds, or other underlying health problems, MRSA is extremely dangerous. MRSA also tends to be found within hospitals where S. aureus is constantly exposed to antibiotics, and therefore able to mutate and evolve to develop resistance.

Why is antibiotic resistance such a problem?

With widespread use of antibiotics, bacteria are constantly subjected to evolutionary challenges. With a rapid rate of mutation, bacteria can develop systems to aid survival incredibly quickly. Eventually, strains of bacteria emerge that cannot be treated with any known antibiotic; then previously perfectly manageable conditions may become life-threatening diseases. Vancomycin-resistant-MRSA is an example of this. Other examples of diseases in which drug resistance has become the predominant challenge to treatment are tuberculosis and malaria (previously this disease could be controlled using quinines; now resistance has lead to the need for a vaccine).

How can development of antibiotic resistance be prevented?

The first and most important step is to limit the unnecessary exposure of bacteria to bactericidal antibiotics; prescription of antibiotics that are not essential has lead to the opportunity for bacteria to evolve and develop avoidance systems. Secondly, it is vital that patients finish their courses of antibiotics, in order to ensure that enough of the invading bacteria are destroyed, limiting the possibility of survival and evolution.

Neoplastic resistance

Resistance is not only limited to microorganisms. Cancer tumour cells may also develop drug efflux pumps to reduce the accumulation of chemotherapeutic agents within the cell. This has been shown to be a major barrier to current cancer treatments; by the time that tumours are identified, most or many of the cells they contain will have developed mutations that may make them less susceptible to the cytotoxic effects of chemotherapeutic drugs.

This article can also be viewed on TJC Oxford.

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