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DRUG RESISTANCE IN APICOMPLEXAN PARASITES 399 DRUG RESISTANCE IN APICOMPLEXAN PARASITES Plasmodium and chemotherapy Of all parasitic diseases, malaria is at the forefront in terms of its ability to inflict devastating effects on the human population. In fact it has been eloquently argued that malaria represents one of the most profound influences in the shaping of the human genome, so devastating is its impact on human survival. Despite the optimistic ambitions of the 1960s to completely eradicate malaria, it is now clear that eradication is not realistically achievable. Furthermore, the gradual erosion in the effectiveness of all available control measures has seen a resurgence in the incidence of malaria worldwide. FIGURE 16.1 Main biochemical drug resistance mechanisms. A simplified scheme of drug-resistance mechanisms found in parasites is illustrated. Specific examples of each type of mechanism are discussed in the text. MEDICAL APPLICATIONS
400 DRUG RESISTANCE It is now estimated that almost half of the world population is at risk from malaria. This risk <strong>trans</strong>lates into an annual incidence rate of some 400 million clinical cases and between 1.5 and 2.7 million deaths. Almost all of these deaths are due to infection with Plasmodium falciparum. Moreover the burden of this mortality is seen in sub-Saharan Africa with young children and pregnant mothers, deficient in an adequate immune response to infection, being by far the most at-risk groups. Efforts to control malaria by targeting the mosquito vector continue, but represent a measure that at best may reduce malaria incidence. Malaria vaccines may offer a long-term solution to this disease but as yet a suitable vaccine remains many years away. Thus our principal tool in the control and treatment of malaria is chemotherapy. The practice of malaria chemotherapy has been in operation over many centuries. Despite this, as we enter the twenty-first century we find ourselves with only a handful of anti-malarial drugs with potential clinical utility. Moreover, parasite resistance to almost all of these drugs has been identified in wild parasite populations present in endemic areas of the world. As with all parasitic diseases targeting resource-poor areas of the world, the situation is exacerbated by issues of drug affordability and drug access. Drug resistance in malaria is a major challenge. Failure to understand the factors contributing to resistance development in the field and failure to elucidate the basic biological mechanisms of resistance will have a devastating impact on our ability to deal with this lifethreatening infection. Chloroquine The 4-aminoquinoline chloroquine (Figure 16.2) was introduced into clinical medicine in the 1940s and was the mainstay of malaria control efforts until the development and spread of resistance to the drug. Despite a general perception to the contrary there remain areas of the world where chloroquine is still effective. Furthermore, chloroquine remains the first choice anti-malarial drug in many parts of the world even where its clinical effectiveness has been seriously eroded. Against a parasitesusceptible backdrop, chloroquine’s success can be explained in terms of its affordability, safety (when used as indicated), ease of use and effectiveness. Chloroquine’s principal target is the intraerythrocytic feeding trophozoite stage. The concept of chloroquine resistance was not generally appreciated until some 15–20 years after the drug’s clinical introduction. It was not until the late 1950s that reports of clinical failure of chloroquine were reported independently from SE Asia and South America. Since these initial reports chloroquine resistance has gradually spread to encompass all malaria endemic regions of the world, with the late 1970s marking the period when resistance reached East Africa. In order to fully understand chloroquine resistance it is important to recognize that resistance acquisition took many years to develop. Even then it only occurred in a limited number of geographical foci with their own <strong>trans</strong>mission characteristics and chloroquine treatment experiences. This contrasts with drugs such as pyrimethamine, where resistance has developed quickly and independently on a number of occasions. This difference must reflect the relative complexity of the chloroquine resistance mechanism compared to the simple point mutations in dhfr that are associated with reduced pyrimethamine sensitivity. Parasites are generally referred to as chloroquine-resistant or chloroquine-sensitive. This definition may be acceptable from a clinical stance, but from a biological perspective it fails MEDICAL APPLICATIONS
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Molecular Medical Parasitology
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Molecular Medical Parasitology Edit
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Contents List of contributors Prefa
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List of contributors Mark Blaxter,
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LIST OF CONTRIBUTORS ix Richard. J.
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Preface Parasitology was born as th
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S E C T I O N I MOLECULAR BIOLOGY
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C H A P T E R 1 Parasite genomics M
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TABLE 1.1 Parasite genomes: genome
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GENERATING GENOMICS DATA 7 differen
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GENERATING GENOMICS DATA 9 TABLE 1.
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GENERATING GENOMICS DATA 11 called
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GENERATING GENOMICS DATA 13 200 000
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BIOINFORMATICS AND THE ANALYSIS OF
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THE POST-GENOMICS ERA, AND THE OTHE
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THE PARASITES AND THEIR GENOMES 19
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FURTHER READING 27 treated with a d
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C H A P T E R 2 RNA processing in p
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TRANS-SPLICING 31 cis trans Exon 1
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TRANS-SPLICING 33 snRNPs (small nuc
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TRANS-SPLICING 35 trans cis U2AF35
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RNA EDITING 37 P AAAA... AAAA... AA
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RNA EDITING 39 entire transcript re
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RNA EDITING 41 5 Editing block C Ed
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RNA EDITING 43 microscopy) approach
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FURTHER READING 45 Nilsen, T.W. (19
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C H A P T E R 3 Transcription Arthu
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UNUSUAL MODES OF TRANSCRIPTION IN T
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CLASS I TRANSCRIPTION IN TRYPANOSOM
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CLASS II TRANSCRIPTION OF PROTEIN C
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SL RNA AND U snRNA GENE TRANSCRIPTI
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FURTHER READING 65 and switching in
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C H A P T E R 4 Post-transcriptiona
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POST-TRANSCRIPTIONAL REGULATION IN
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FURTHER READING 87 inhibition, it m
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C H A P T E R 5 Antigenic variation
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ANTIGENIC VARIATION AT THE STRUCTUR
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ANTIGENIC VARIATION AT THE STRUCTUR
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VSG Signal sequence Amino-terminal
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GENETICS OF ANTIGENIC VARIATION 97
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IMMUNE RESPONSES TO TRYPANOSOME INF
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INNATE RESISTANCE, HUMAN SUSCEPTIBI
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ANTIGENIC VARIATION IN MALARIA 107
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FURTHER READING 109 ACKNOWLEDGEMENT
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C H A P T E R 6 Genetic and genomic
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‘FORWARD’ VS. ‘REVERSE’ GEN
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EXAMPLES OF ‘FORWARD’ GENETIC A
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EXAMPLES OF ‘FORWARD’ GENETIC A
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REVERSE GENETICS AND LEISHMANIA VIR
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VALIDATION OF CANDIDATE VIRULENCE G
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S E C T I O N II BIOCHEMISTRY AND C
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C H A P T E R 7 Energy metabolism P
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SUBCELLULAR ORGANIZATION OF AMITOCH
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CELL MEMBRANE Fructose [b] Glucose
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STEPS OF AMITOCHONDRIATE CORE METAB
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ENZYMATIC DIFFERENCES BETWEEN AMITO
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ACTION OF NITROIMIDAZOLE DRUGS 135
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ENVOI 137 unambiguously reflect the
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FURTHER READING 139 Saavedra-Lira,
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THE EMBDEN-MEYERHOF-PARNAS (EMP) PA
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WHY DO TRYPANOSOMATIDAE HAVE GLYCOS
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FURTHER READING 153 for use in agri
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CARBOHYDRATE METABOLISM 155 as a hu
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158 ENERGY METABOLISM - APICOMPLEXA
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172 PROTEIN METABOLISM PROTEINS (1)
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174 PROTEIN METABOLISM the C-termin
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176 PROTEIN METABOLISM and also, to
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178 PROTEIN METABOLISM values rangi
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180 PROTEIN METABOLISM of the plasm
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182 PROTEIN METABOLISM in vivo, in
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184 PROTEIN METABOLISM PROLINE Poly
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186 PROTEIN METABOLISM CO 2 Dec-SAM
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188 PROTEIN METABOLISM a cMDH has b
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190 PROTEIN METABOLISM Urea ARGININ
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192 PROTEIN METABOLISM been describ
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194 PROTEIN METABOLISM absence of g
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198 PURINES AND PYRIMIDINES enable
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200 PURINES AND PYRIMIDINES provide
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202 PURINES AND PYRIMIDINES activit
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204 PURINES AND PYRIMIDINES physiol
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206 PURINES AND PYRIMIDINES Amitoch
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208 PURINES AND PYRIMIDINES their a
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210 PURINES AND PYRIMIDINES FIGURE
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214 PURINES AND PYRIMIDINES protein
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220 PURINES AND PYRIMIDINES in Plas
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222 PURINES AND PYRIMIDINES whereas
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226 TRYPANOSOMATID CARBOHYDRATES AF
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228 TRYPANOSOMATID CARBOHYDRATES In
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230 TRYPANOSOMATID CARBOHYDRATES po
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232 TRYPANOSOMATID CARBOHYDRATES LP
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234 TRYPANOSOMATID CARBOHYDRATES re
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236 TRYPANOSOMATID CARBOHYDRATES sc
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A. sAP COOH [T][T](S/T)(S/T)(S/T)SS
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240 TRYPANOSOMATID CARBOHYDRATES Cr
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242 INTRACELLULAR SIGNALING protein
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244 INTRACELLULAR SIGNALING FIGURE
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246 INTRACELLULAR SIGNALING 212.5 2
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248 INTRACELLULAR SIGNALING cycle.
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250 INTRACELLULAR SIGNALING V-H -A
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252 INTRACELLULAR SIGNALING domain)
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254 INTRACELLULAR SIGNALING the kno
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256 INTRACELLULAR SIGNALING from in
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258 INTRACELLULAR SIGNALING FIGURE
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260 INTRACELLULAR SIGNALING ESAG4 (
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262 INTRACELLULAR SIGNALING and ind
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264 INTRACELLULAR SIGNALING ATPase
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266 INTRACELLULAR SIGNALING G11XG
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268 INTRACELLULAR SIGNALING a diffe
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270 INTRACELLULAR SIGNALING rapid l
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272 INTRACELLULAR SIGNALING cells w
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274 INTRACELLULAR SIGNALING PfPPJ i
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276 INTRACELLULAR SIGNALING is cont
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278 PLASTIDS, MITOCHONDRIA, AND HYD
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298 HELMINTH SURFACES Important exc
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300 HELMINTH SURFACES protease inhi
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302 HELMINTH SURFACES volume, there
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304 HELMINTH SURFACES projecting si
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306 HELMINTH SURFACES schistosome t
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308 HELMINTH SURFACES re-establish
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310 HELMINTH SURFACES hepatic cells
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312 HELMINTH SURFACES lungs. Larvae
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314 HELMINTH SURFACES cuticle, whic
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316 HELMINTH SURFACES cuticle in th
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318 HELMINTH SURFACES mec-8 or sym-
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320 HELMINTH SURFACES current, when
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322 HELMINTH SURFACES The cuticle-h
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324 HELMINTH SURFACES are typically
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326 HELMINTH SURFACES or carrier pr
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328 HELMINTH SURFACES of tyrosine-b
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330 HELMINTH SURFACES blood. The ge
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332 HELMINTH SURFACES Mutations in
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334 HELMINTH SURFACES in the hypode
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336 HELMINTH SURFACES (including H-
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338 HELMINTH SURFACES Blaxter, M.L.
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340 ENERGY METABOLISM IN HELMINTHS
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Page 361 and 362: 348 ENERGY METABOLISM IN HELMINTHS
Page 373 and 374: 360 NEUROTRANSMITTERS CO 2 H NH 2 G
Page 375 and 376: 362 NEUROTRANSMITTERS TABLE 15.1 An
Page 377 and 378: 364 NEUROTRANSMITTERS more arms tha
Page 379 and 380: 366 NEUROTRANSMITTERS the surroundi
Page 381 and 382: 368 NEUROTRANSMITTERS proteins requ
Page 383 and 384: 370 NEUROTRANSMITTERS FIGURE 15.11
Page 385 and 386: 372 NEUROTRANSMITTERS FIGURE 15.13
Page 387 and 388: 374 NEUROTRANSMITTERS sensitivity t
Page 389 and 390: 376 NEUROTRANSMITTERS TABLE 15.3 Cl
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Page 395 and 396: 382 NEUROTRANSMITTERS C-terminals a
Page 397 and 398: 384 NEUROTRANSMITTERS Davis and Str
Page 399 and 400: 386 NEUROTRANSMITTERS Cephalic gang
Page 401 and 402: 388 NEUROTRANSMITTERS myoexcitation
Page 403 and 404: 390 NEUROTRANSMITTERS is phosphoryl
Page 405 and 406: 392 NEUROTRANSMITTERS many other an
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Page 411: 398 DRUG RESISTANCE of some of the
Page 415 and 416: 402 DRUG RESISTANCE is again assume
Page 417 and 418: 404 DRUG RESISTANCE An alternative
Page 419 and 420: 406 DRUG RESISTANCE clinical eviden
Page 421 and 422: 408 DRUG RESISTANCE FIGURE 16.4 Fol
Page 423 and 424: 410 DRUG RESISTANCE Using similar s
Page 425 and 426: 412 DRUG RESISTANCE whether these r
Page 427 and 428: 414 DRUG RESISTANCE FIGURE 16.5 Str
Page 429 and 430: 416 DRUG RESISTANCE FIGURE 16.6 Try
Page 431 and 432: 418 DRUG RESISTANCE has permitted e
Page 433 and 434: 420 DRUG RESISTANCE FIGURE 16.7 Dru
Page 435 and 436: 422 DRUG RESISTANCE near future. Th
Page 437 and 438: 424 DRUG RESISTANCE million new inf
Page 439 and 440: 426 DRUG RESISTANCE some 50 million
Page 441 and 442: 428 DRUG RESISTANCE pharynx, the bo
Page 443 and 444: 430 DRUG RESISTANCE efforts for glo
Page 445 and 446: 432 DRUG RESISTANCE and resistance
Page 447 and 448: 434 MEDICAL IMPLICATIONS TABLE 17.1
Page 449 and 450: 436 MEDICAL IMPLICATIONS TABLE 17.1
Page 451 and 452: 438 MEDICAL IMPLICATIONS transmissi
Page 453 and 454: 440 MEDICAL IMPLICATIONS H 2 C H H
Page 455 and 456: 442 MEDICAL IMPLICATIONS parasites
Page 457 and 458: 444 MEDICAL IMPLICATIONS neuropsych
Page 459 and 460: 446 MEDICAL IMPLICATIONS of toxic f
Page 461 and 462: 448 MEDICAL IMPLICATIONS Future con
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450 MEDICAL IMPLICATIONS Melarsopro
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452 MEDICAL IMPLICATIONS prevention
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454 MEDICAL IMPLICATIONS resulting
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456 MEDICAL IMPLICATIONS for S. ste
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458 MEDICAL IMPLICATIONS are though
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460 MEDICAL IMPLICATIONS FIGURE 17.
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462 MEDICAL IMPLICATIONS Marr, J.J.
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464 INDEX Aldolase, 143 Plasmodium
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466 INDEX Ascofuranone, 143 ASCUT-1
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468 INDEX Cnidarians, RNA trans-spl
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470 INDEX Entamoeba, 125 Ca 2 metab
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472 INDEX Glucose-6-phosphate dehyd
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474 INDEX Ivermectin, 398, 427, 455
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476 INDEX Maduramicin, 412 Major va
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478 INDEX Nitric oxide: neurotransm
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480 INDEX calcium-binding proteins,
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482 INDEX Pyrimidine transport, 200
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484 INDEX Succinate:rhodoquinone ox
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486 INDEX genome, 21 survey sequenc
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488 INDEX U small nuclear RNA (snRN
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