Molecular Mechanism of Drug Resistance - Coursework Example

RUNNING HEAD: MOLECULAR MECHANISM OF DRUG RESISTANCE Molecular Mechanism of drug resistance [Name of the Writer] [Name of the Institution] Molecular Mechanism of Drug Resistance Introduction Antimicrobial agents are those material or drugs through antiviral, antifungal, antibiotic and antiparasitic characteristics. According to the World Health Organization, antimicrobial agents have considerably reduced the risk posed by infectious diseases as their invention in the twentieth century. The utilisation of these "wonder drugs", joint with improvements in hygiene, housing, and nourishment, and the advent of common immunization programmes, has led to a vivid drop in fatalities from diseases that were earlier widespread, not curable, and frequently deadly. (Suller, 2000 p. 11-18) Over the years, such causes have saved the lives and relieved the distress of millions of people and have assisted in bringing many severe infectious diseases under power. These drugs have also added to the main gains in life anticipating experienced during the later part of the last century. However, these increases are now sincerely jeopardized by another new development: the appearance and increase of microbes that are resistant to contemptible and helpful first-choice, or "first-line" drugs. (Suller, 2000 p. 11-18) As an outcome of this, it has been suggested that the practice of antimicrobial agents by persons is preferable when approved by a skilled physician since an overdo (or under-use), can spread resistant microbial variants and antimicrobial resistance is ensuing in bigger morbidity, mortality, and health-care costs In general, basic mechanisms of antibiotic resistance include microbial cell impermeability, target site modification, enzymatic modification or destruction of the antibiotic and its increased efflux. Because of the increasing emergence of resistance, major efforts are devoted to combat the resistance by combining lincosamides with other agents. The genetic background of drug resistance is well described and methods for genotypic susceptibility testing have been developed. (Suller, 2000 p. 11-18) The rise of macrolide- and lincosamide-resistant strains of pathogenic Gram-positive cocci over the past decades has changed treatment guidelines and induced the researchers to detect new resistance mechanisms that may profoundly affect the clinical outcome. The rise and dissemination of common macrolide and lincosamide resistance mechanismsthat have been identified in Staphylococcus and Streptococcus species of clinical interest have been discussed in detail by. (Suller, 2000 p. 11-18) The studies on the insect’s defensive mechanisms against various pathogens like bacteria, fungi, protozoa are well documented. However, the mechanisms by which insects fight and recognize viral infections are still poorly understood. One important part of self defence system in insects sustains the antiviral peptides. The one important AMPs effect is the modulation of the innate immune system and its response in host organism. (Matanick, 2004 p. 382-389) Peptides originated from one animal species and specifically modulated immune response in another is defined as allergenic cytokines. To this group belong alloferons. Peptides, like alloferons, are able to stimulate natural killer cells (NK) activity and interferon’s (IFN) synthesis in animal and human models. NK cells are known to be the crucial element of the antiviral and the antitumor innate immunity shared by vertebrates and some invertebrates. (Matanick, 2004 p. 382-389) The both mechanisms work in close cooperation: the activation of natural killing and IFN production. Whereas interferons stimulate NK cell cytotoxicity, NK cells produce IFNs on stimulation. (Matanick, 2004 p. 382-389) Antimalarial Drug Resistance Malaria parasites belong to the genus Plasmodium. There are four species of Plasmodium that affect man, of which P. falciparum is the most severe, taking responsibility for almost all of the mortality due to malaria. P. vivax is the most prevalent parasite outside tropical Africa, causing morbidity and economic losses, but is nowadays rarely lethal. Although there are malaria parasite species that affect many mammals, birds and reptiles, human malaria parasites infect only man and some non-human primates; the latter are not considered to be a significant animal reservoir of disease. Human malaria parasites are believed to have arisen in Africa thousands of years ago, and moved with the spread of agriculture to nearly all of the tropical, sub-tropical and temperate regions of the world (Carter and Mendis, 2002 p. 569-594). By the mid-19th century, well over half, and perhaps as much as 80%, of the population of the world was at significant risk of malaria. In late medieval Britain, malaria was endemic and severe in the English fens and other marshy areas of England, especially the estuaries of the Solway, Thames and Medway. During the first half of the twentieth century, improved living conditions, cheap and effective antimalarial drugs, and mosquito control programmes all helped to eliminate malaria from the United States and most of Europe. Continuing efforts after the Second World War, including extensive mosquito control programmes with insecticides such as DDT, reduced malaria-related mortality from the Mediterranean to the Western Pacific. At the dawn of the 21st century, malaria remains a major cause of death only in Africa. Despite progress elsewhere, sub-Saharan Africa has seen a steady rise in the number of cases and the number of deaths from malaria since the late 1980s. There are many reasons for this, including large population movements, environmental and climatic changes, war and civil disturbance, and uncontrolled development activities. However, by far the most important factor in the rise of malaria morbidity is the development by the parasiteP. falciparum of resistance to the commonly used antimalarial drugs, chloroquine and sulfadoxinepyrimethamine (SP). Who Dies From Malaria? Over one million people die from malaria each year. Nine out of ten of these deaths occur in Africa, in the tropical regions south of the Sahara desert. Children under the age of five are most at risk. Pregnant women, whose immunity is suppressed, especially in their first pregnancy, are also at risk of death, abortion or still-birth. Malaria causes at least 20% of the deaths of children under the age of five in Africa (World Health Organisation, 2003). A child living in a malaria-endemic region, such as Senegal, has an average of 24 malaria attacks by the time they reach the age of five, and some children may have as many as 40 attacks in this period (Trape et al, 2002 224-230). Prompt and effective diagnosis and treatment of malaria can prevent progression of the disease to severe malaria and death. Without effective treatment, severe malaria case fatality rates can be as high as 30%. In the United Kingdom and the rest of non-malarious Europe, imported malaria is a growing public health issue. Most imported malaria is acquired in Africa and 70% is due to P. falciparum. The number of European imported cases has increased from a few thousand cases annually in the early 1970s, to 15 000 cases in 2000 (www.who.dk/ malaria/ctryinfo/). In the UK, there are 2000 cases per year on average, and around 10 deaths. How Does Drug Resistance Arise and Spread? Antimalarial drug resistance is firmly defined as the aptitude of a parasite pull to survive and/or grow, despite the direction and amalgamation of a drug given in doses identical to or advanced than those typically suggested, but within the limitations of tolerance of the subject. Resistance to antimalarial drugs has now been depicted for two of the four classes of malaria parasite that obviously contaminate humans, P. falciparum and P. vivax. The condition is mainly grave for P. falciparum, which has built resistance to almost all of the antimalarials in existing use, although the environmental division of resistance to any solitary drug differs greatly. Drug resistance comes as a result of spontaneously happening changes in precise parasite genes. These changes change the arrangement and/or movement of the drag goal in the malaria parasite. The admission of the drug to the target can also be exaggerated by genetic change, for example by changes in drug transporters. Parasites shipping certain genetic alterations are capable to survive in patients who have acknowledged an antimalarial drug, while the 'wild-type' parasites do not. Parasites that are resistant to the chemotherapeutic mediator therefore boost in frequency in the population, a process known as drug collection. Drug resistance can spread from one area to another in two ways. Mosquitoes carrying drug-resistant parasites can spread resistance on a small scale, but their flight ranges are restricted to a few kilometres. A more important method is the movement of infected people from an area of high drug resistance to one of low or no resistance. Human migration was probably an important factor in the increase of chloroquine resistance between diverse endemic regions of Asia and Oceania, and for the initial introduction of chloroquine resistance into East Africa. Drugs with a long elimination time from the body (half-life), such as the commonly used prophylactic drug mefloq (Lariam®), persist at sub-therapeutic concentrations in the plasma for many weeks after the initial Plasmodium infection has been cleared. If the person becomes reinfected during this period, parasites will be exposed to the drug at levels which will not kill them, but which may encourage the development of resistant parasites (Wernsdorfer, 1994 p. 143-156). The widespread use of antimalarial drugs is considered to be a major reason for the rapid spread of resistance. As the number of individuals in an area taking a particular antimalarial drug increases, so does the probability that parasites will be uncovered to insufficient drug levels, and resistant mutants are more readily selected. The extent of drug use also influences the spread of resistant parasites once they have arisen, since only resistant parasites will survive in individuals receiving the correct dose of drug. Generally, it has been observed that resistance rates are higher in urban areas than in rural areas, presumably reflecting the greater access to, and use of, drugs. The distribution in the 1950s of 'medicated table salt' containing chloroquine along the Thai-Cambodian border is a good example of inappropriate drug use leading to the rapid expansion of drug-resistant parasites. The intense drug pressure, coupled with likely sub-therapeutic levels in some individuals, may have played a role in the emergence of chloroquine resistance in this area in the late 1950s. Resistance to chloroquine in P. falciparum Chloroquine was introduced for treatment and control of malaria in the 1940s and quickly became the drug of choice for most malaria-endemic countries. The drug causes very few side-effects, mostly mild in nature, and is safe for use, even in children and pregnant women. Importantly it is also cheap in comparison to most modem drugs. Chloroquine treatment failure was first reported in Colombia and, as mentioned above, at the Cambodia-Thai border in the late 1950s, approximately 12 years after it was first introduced. Resistance spread rapidly (Wongsrichanalai et al., 2002 p. 209-218) and is now widespread in most malaria endemic countries. In East Africa, the drug fails to clear parasitaemia in more than 50% of treated patients. Chloroquine has now been withdrawn as the official first-line treatment for uncomplicated malaria in some African countries. Chloroquine works by interfering with the detoxification processes in the parasite. Malaria parasites live within red blood cells and obtain some nutrients by breaking down haemoglobin. Haemoglobin is digested within the parasite's food vacuole releasing harm in its poisonous haematin form, in large amounts. Haematin is usually detoxified by polymerisation to form insoluble crystals of haemozoin, also known as malaria pigment. Chloroquine accumulates in the food vacuole, and interrupts this haematin detoxification. It is thought that the drug binds to the haematin and also to the haemozoin crystals themselves, preventing polymerisation and forming toxic complexes that cause parasite death. Less chloroquine accumulates in the food vacuole of drug-resistant than of drug-sensitive parasites. Mutations in a parasite gene called Pfcrt (P. falciparum chloroquine resistance transporter) have been associated with chloroquine resistance (Wellems and Plowe, 2001 p. 770-776). Pfcrt encodes a transporter-like protein that localises to the food vacuole membrane, and which may be involved in ding flux and/or pH regulation. However, the presence of the mutated form of Pfcrt cannot be used to predict chloroquine treatment failure. In some areas, mutant Pfcrt is found in auk or nearly all parasites, yet chloroquine can still be effective in some patients. In Mali, for example, chloroquine treatment cured 60% of adults and older children who had parasites with the mutant form of Pfcrt. The ability of people to eliminate resistant parasites increased with age implying that immunity plays an important role in the clearance of chloroquine resistant parasites. Mutations in another gene called Pfmdrl may play a modulatory role in chloroquine resistance (Wongsricbanalai et ai, 2002). Pfmdrl encodes an ABC-type membrane transporter, which may be involved in altering flux of the drug into or out of the food vacuole. This is akin to mammalian tumour cells exhibiting a multidrug-resistance (mdr) phenotype, responsible for expulsion of a wide range of inhibitors. Resistance of P. falciparum Xo other commonly used antimalarial drugs Quinine and mefioquine Resistance to the chloroquine-like compounds mefioquine and quinine is restricted to Southeast Asia. Mefioquine was first introduced in 1977, and resistance was reported from the Thai-Myanmar and the Thai-Cambodian borders in 1982. Quinine has been in use since the 17th century, and resistance was first reported in 1910. The mode of action of quinine and mefioquine are believed to be similar to that of chloroquine, but the mechanisms of resistance are different. Some in vivo studies have shown associations between resistance to mefioquine and quinine, whereas others have not. The mechanism of resistance to these drugs probably involves alterations in the sequence and copy number of the Pfmdrl gene. Antifolates Antifolates are antimalarial drugs that target enzymes in the folate pathway of the parasite. Antifolates, such as the drug combination sulfadoxine-pyrimethamine (SP), act by sequential and synergistic blockage of two important enzymes in the folate synthesis pathway. Pyrimethamine inhibits dihydrofolate reductase (DHFR), and sulfadoxine inhibits dihydropteroate synthetase IDHPS). These enzymes are essential for the provision of nucleotides for DNA synthesis and for amino acid metabolism. Antifolate drugs, therefore, act to prevent DNA replication, and hence inhibit parasite multiplication. SP is cheap for a full adult treatment) and has often replaced chloroquine as the first-line antimalarial in countries where resistance to chloroquine is high. Resistance to SP was first reported in the early 1960s on the Thai-Cambodian border (Wongsricbanalai et al., 2002). SP resistance in East Africa is increasing, and given the increased selection pressure following its choice as a first line drug in this area, is likely to increase still further. P falciparum resistance to SP is primarily awarded by consecutive single-point changes in parasite dhfr, which encodes DHFR, and by added mutations in dhps, which encodes DHPS. These mutations directly affect the binding of the inhibitory drugs to the enzyme targets, with little effect on the binding of the natural substrate (Hyde, 2002 p. 165-174). Clinical resistance to the drug combination SP in vivo seems to require mutations in both dhfr and dhps, although the correlation between treatment failure and the presence of different mutant parasites is contentious. Parasites that have three specific point mutations in dhfr, combined with at least two in dhps, are highly correlated with treatment failure with SP. However, the association of treatment outcome for parasites with lower levels of mutation in these genes is much less certain. Malarone The synergistic combination of the antifolate drug, proguanil, and another agent called atovaquone is known as Malarone®. Malarone is commonly used prophylactically for the prevention of malaria in travelers. Resistance to the antifolate, cycloguanil, the active metaholite of proguanil, is the result of mutations in dhfr. Atovaquone inhibits electron transport at the cytochrome bi complex in the parasite mitochondrion, but does not affect the host mitochondrial functions at the doses used. Resistance to atovaquone expands very quickly when it is used alone, but more slowly when used in combination with other drugs. Resistance is conferred by single or double point mutations in the parasite cytochrome b icyth) gene. There have been very limited reports of Malarone resistance in Africa. Drug resistant P. vivax p. vivax causes 75 - 90 million cases of non-fatal disease annually (Mendis et ai, 2001 p. 97-106), most of which are outside Africa. Infections are usually treated with chloroquine and primaquine, the latter is used specifically to treat hypnozoites, a dormant stage in the liver that is responsible for the relapses observed in P. uivax. Chloroquine-resistant P. vivax was first reported in Papua New Guinea (PNG) in 1989, nearly 30 years after the discovery of chloroquine-resistant P. falciparum, despite similar levels of chloroquine use for treatment of the two species. By the early 1990s, treatment with chloroquine was unsuccessful in 227r of patients in a field trial in PNG. More recently, nearly 50% of infections in this area showed reduced susceptibility to chloroquine. Resistance has also been reported in Southeast Asia and South America (Whithy, 1997), There are also reports of resistance to primaquine. The mechanism of resistance to chloroquine and primaquine is unknown. What is the impact of drug resistance on malaria mortality? The increase in chloroquine resistance in Africa has coincided with a doubling (or more) of malaria mortality, notably amongst children (Trape et al., 2002 224-230). Antimalarial drug resistance has also been concerned in the rising frequency and strictness of epidemics. One dramatic study highlights the impact of chloroquine resistance on malaria mortality (Trape et al., 2002 p. 224-230). In the period before chloroquine resistance, malaria mortality in Casamance in Senegal, an area of 11 villages in forests, housing around 7600 inhabitants, was very low, at 0.5 deaths per 1000 children under five years old per year. The first cases of chloroquine resistance were noted in 1990, and by the following year, half of the P. falciparum infections were not responding to chloroquine. Malaria mortality increased eleven-fold in children under the age of five. Children died because they were treated first with chloroquine, and when this failed, they progressed too rapidly to severe disease and death for alternative treatments to the found and administered. Over 70% of deaths occurred within one week of treatment failure. Where Do We Go From Here? Prompt and effective treatment of malaria is critical for the control of malaria. Antimalarial drug resistance is one of the biggest challenges of malaria control today. Currently less than 45% of children fewer than five years receive the treatment they require, and many of these receive chloroquine, which is rapidly losing its effectiveness. It is likely that the replacement drug, sulfadoxine-pyrimethamine, will not retain its usefulness for much longer. Despite the seriousness of the malaria problem, there are few new things in development. Many of the chemotherapeutic agents in use today date from research begun during the Second World War and the Vietnam War. The most recently introduced antimalarial drugs, the artemisinin derivatives, are also in some senses the oldest, Artemisinin are based on the antimalarial qinghaosu, an extract of Artemisia annua (Wormwood). The drug has been used for more than 2000 years in China, but only came to the attention of the Western world in the 1970s; these drugs have enormous potential, but need to be used wisely to delay resistance. They are already saving lives, but they are not currently widely available, and are expensive - unaffordable for many afflicted. Experience with drug treatment of TB and HIV infection highlights the importance of combination therapy to delay the development of resistance. The parasite has to mutate in several separate sites simultaneously to become resistant to a combination. For malaria, new combinations of old drugs are being used i.e., chlorproguanil-dapsone (LAP-DAP), as well as combinations of new drugs such as the artemisinin. However, the efficiency of the old drug combinations may be short-lived, as the resistance mutations already exist in the parasite population. It is obvious that new drugs are needed. Unfortunately, malaria is a disease of poverty, and despite much scientific knowledge, there is an insufficient market incentive to interest the tig Phamia'. Recognising this, the Medicines for Malaria Venture (MMV) was established to bring together academic and industrial scientists to identify suitable targets and develop new drugs (Ridley, 2002 p. 686-693); MMV currently has 15 projects developing new drugs in various stages of development, several of which are in clinical trials. The future for malaria control does not lie solely with antimalarial chemotherapy, and other methods of control are proving highly effective in some areas. Insecticide treated bed nets and curtains protect against malaria, reducing the number of deaths in young children by as much as 20% (World Health Organisation, 2003). Much scientific research has concentrated on vaccine development, and some candidate vaccines have been tested in clinical trials, some with promising results (Richie and Saul, 2002 p. 694-701). Realistically an effective vaccine is still some way off. Until that time chemotherapy will remain the mainstay of malaria control programmes, and drug resistance an unfortunate fact of life. References Carter R and Mendis K N (2002) Evolutionary and historical aspects of the burden of malaria. Clinical Microbiology Reviews, 15, 564 - 594. Hyde J E (2002) Mechanisms of resistance of Plasmodium falciparum to antimalarial drugs. Microbeff and Infection. 4,165 - 174. Matanick, lbiol, V.C. and Castilla, V. (2004) Inter. J. Antimicrob. Agents, 23, 382-389. Mendis K et al. (2001) The neglected burden of Plasmodium vivax malaria. American Journal of Tropical Medicine and Hygiene, 64, 97 - 106. Richie T L and Saul A (2002) Progress and challenges for malaria vaccines. Nature, 415. 694 - 701. Ridley R G (2002) Medical need, scientific opportunity and the drive for antimalariai drugs. Nature. 415, 686 - 693. Suller MT, Russel AD. Triclosan and antibiotic resistance in staphylococcus aureus. Journal Antimicrobial Chemotherapy 2000; 46: 11- 18. Trape J F et al. (2002) Combating malaria in Africa. Trends in Parasitology, 18, 224 - 230. Wellems T E and Piowe C V (2001) Chloroquine-resistant malaria. Journal of Infectious Diseases. 184, 770 - 776. Wernsdorfer W (1994) Epidemiology of drug resistance in malaria. Acio Tropica, 56, 143- 156. Whitby M (1997) Drug resistant Plasmodium vivax malaria. Journal of Antimicrobial Chemotherapy, 40, 749 - 752. Wongsrichanalai C et al. (2002) Epidemiology of drug-resistant malaria. Lancet Infectious Diseases. 2, 209 - 218. World Health Organisation (2003) Africa Malaria Report 2003. Read More