Emergence of Drug Resistance
The WHO defines antimalarial drug resistance as "the ability of a parasite strain to survive and/or multiply despite the proper administration and absorption of an antimalarial drug in the dose normally recommended." Resistance develops in two phases: the initial genetic event where resistance mutations occur; and the ensuing process where the survival advantage developed by the mutants in the presence of the drug results in their preferential transmission, thus spreading resistance. In the absence of antimalarial medicines, the mutants could potentially be at a survival disadvantage. Microbial resistance occurs as a result of random mutations that interfere with a given drug's mechanism of action. For example, if a drug's action depends on binding to a specific protein in the infectious agent, a random mutation might result in a slight alteration in the shape of the protein such that binding can no longer occur. Another drug might inhibit DNA replication within the parasite. Random mutations that render an infectious agent resistant to a particular drug are rare, but they are virtually inevitable given a large enough number of DNA replications in a parasitic species.
Resistance to antimalarial drugs is a major threat to malaria control and has been documented in all classes of antimalarials, including the artemisinin derivatives. P. falciparum resistance to chloroquine first emerged in the late 1950's in South East Asia and spread to other areas in Asia and then to Africa in the following three decades. Resistance to sulfadoxine-pyrimethamine originated in the same area of South East Asia and spread rapidly to Africa. In the Amazon region of South America, resistance to chloroquine and sulfadoxine-pyrimethamine emerged independently and spread throughout the continent. After widespread use, resistance to mefloquine appeared in the Mekong region of Asia within five years of its introduction in the 1990s. Although resistance has forced most malaria endemic countries to abandon chloroquine in P. falciparum treatment, chloroquine remains the first-line treatment for P. vivax. However, this treatment is being threatened by the emergence and spread of chloroquine resistant strains of that parasite.
Watch a video showing the spread of resistance and an interesting DNA tracking project
Virulence factors are those factors that increase the damaging effects of an infective organism. They serve to make the organism more infectious, increase its ability to invade, increase its evasiveness to immune response, or worsen the severity of disease. Drug resistance is a special kind of virulence factor that enables the pathogen to survive in the face of normally effective chemotherapy. Organisms typically have several virulence factors expressed at one time, since the "normal" pathogen employs several to invade and establish infection and disease. Drug resistance usually emerges only in the presence of widespread use of a treatment regime, and typically decreases after cessation of this type of treatment.
Drug resistance is typically considered to exact a "biological cost" or a "fitness cost" of an organism. In other words, a mutation that confers the benefit of drug resistance may also have some adverse effects on the pathogen, such as slower growth. As a result, resistance to a given drug may provide a survival advantage only in the continued presence of the drug, i.e., continued presence of a selection pressure that favors drug resistant strains. It has been shown repeatedly that, once certain drugs are discontinued, prevalence of resistance to those drugs also decreases (Stein et al), because discontinuation of the drug removes the selcetion pressure that favored that strain, and the other biological effects of the mutation then put that strain at a competitive disadvantage.
It is widely believed that drug resistance only develops in the presence of inadequate chemotherapy regimes, for example administration of sub-optimal doses that do not eliminate infection but instead select for resistant strains to thrive. Recent work by Schneider et al. suggests an alternate pathway for drug resistance to develop, and these conclusions have far reaching implications for both the development of drug resistance and our ability to combat it. Schneider infected mice with 2 genetically related strains of P. chabaudi, one virulent and one avirulent, and discovered that the virulent strain had a high level of drug resistance to pyrimethamine. The virulent strain had not developed resistance in an environment of low dose administration of the drug, and resistance developed in conjunction with other virulence factors. In essence, the resistance mechanism conferred fitness, rather than exacting a fitness cost on the organism.
Specifically, this case of resistance arose due to the action of pyrimethamine on the organism. It just so happens that the virulent strain had an altered folate biosynthesis pathway, which gave the advantage of faster multiplication. The altered metabolism of the organism makes this change self-sustaining, and does not require any selective pressure to maintain its biological advantage. This change also alters the way the organism interacts with pyrimethamine, making it less susceptible to the drug almost as a side effect of this alteration.
This marks the first known time that drug resistance has developed independently of drug administration, and has conferred additional advantages that allow such strains to thrive, even in the absence of selective pressure from drug therapy. While the scientific community is cautiously regarding this instance as a singular event, due to the nature of this specific pathway and its role in both drug interaction and metabolism.
