Drug Repositioning in the Treatment of Malaria and TB
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REVIEW SPECIAL FOCUS: NEGLECTED DISEASES For reprint orders, please contact [email protected] Drug repositioning in the treatment of malaria and TB The emergence and spread of drug resistance in the malaria parasite Plasmodium falciparum as well as multi- and extremely drug-resistant forms of Mycobacterium tuberculosis, the causative agent of TB, could hamper the control of these diseases. For instance, there are indications that the malaria parasite is becoming resistant to artemisinin derivatives, drugs that form the backbone of antimalarial combination therapy. Likewise, Mycobacterium tuberculosis strains that are multidrug-resistant or extremely drug-resistant to first- and second-line drugs have been associated with increased mortality. Thus, more than ever, new antimalarials and anti-TB drugs are needed. One of the strategies to discover new drugs is to reposition or repurpose existing drugs, thus reducing the cost and time of drug development. In this review, we discuss how this concept has been used in the past to discover antimalarial and anti-TB drugs, and summarize strategies that can lead to the discovery and development of new drugs. Malaria and TB are the two leading causes of been proposed as an alternative. However, the Alexis Nzila1†, Zhenkun Ma2 mortally worldwide, killing approximately two paucity of available antimalarials limits this & Kelly Chibale1 million people annually [1]. Strategies to control strategy. More than ever, new antimalarials are 1University of Cape Town, and manage these two diseases rest primarily on urgently needed. Departments of Chemistry and Clinical Pharmacology and Institute of the use of effective drugs. The combination of isoniazid, rifampicin, Infectious Disease and Molecular In the case of malaria, the WHO has rec- pyrazinamide and ethambutol has been the cor- Medicine, University of Cape Town, Rondebosch 7701, South Africa ommended the use of artemisinin combina- nerstone of first-line TB treatment. However, 2Global Alliance for TB Drug tion therapies (ACTs) as first-line treatment this treatment requires at least a 6-month Development, 40 Wall Street, for uncomplicated malaria with artemether– period, posing the challenge of compliance. In 24th Floor, NY 10005, USA †Author for correspondence: lumefantrine being the first ACT to be intro- addition, the development and spread of multi- E-mail: [email protected] duced into Africa [2]. Pyronaridine/artesunate drug-resistant strains of Mycobacterium tubercu� and piperaquine/dihydroartemisinin combina- losis (Mtb, MDR-TB), strains resistant to at least tions are at late development stages and have two of the most important first-line drugs isoni- reached Phase III/IV clinical evaluation [201]. azid and rifampicin, have become a serious con- However, the emergence of Plasmodium falci� cern. An even more alarming development is the parum parasites resistant to artemisinin deriva- emergence of extensively drug-resistant strains tives has been reported in South East Asia, rais- of Mtb (XDR-TB), which are strains resistant ing concern that this could spread to Africa, to isoniazid and rifampicin, to any fluoroquino- a scenario that would compromise the current lone, and to one (or more) of the three injectable ACT strategies [3]. second-line drugs (i.e., amikacin, kanamycin or Quinine (QN) remains the drug of choice capreomycin) [6]. for the treatment of severe malaria, and it has Multidrug-resistant TB and XDR-TB treat- become the fall-back option for the treatment of ments are extremely difficult, requiring indi- uncomplicated malaria in many countries [202]. vidualized therapy based on drug-sensitivity However, evidence indicates that resistance to tests. Indeed, these treatments are lengthy this drug is also spreading in South Asia [4]. (>18 months), complicated (require 5–7 drugs), This observation led to the investigation of poorly tolerated and extremely expensive, result- artesunate (an artemisinin derivative) as an ing in poor treatment outcomes, especially in alternative to QN for the treatment of severe patients co-infected with HIV [6–8]. In addition, malaria. This drug has proven superior to QN the emergence and spread of XDR-TB have ren- and, thus, has been recommended for the treat- dered possible the unacceptable scenario of the ment of severe malaria [5]. However, the spread inability to clear TB infection using any avail- of artemisinin resistance could also compromise able anti-TB drug regimen. Thus, new drugs this option. To overcome this potential short- with novel mechanisms of action are needed for fall, non-artemisinin-based combinations have the management of MDR- and XDR-TB. 10.4155/FMC.11.95 © 2011 Future Science Ltd Future Med. Chem. (2011) 3(11), 1413–1426 ISSN 1756-8919 1413 REVIEW | Nzila, Ma & Chibale Key Terms Furthermore, effective treatment of TB in infections [11]. Prontosil is a prodrug, which is patients co-infected with HIV is often compro- converted in vivo to the active compound sul- Malaria: Disease caused by a protozoa (apicomplexa) parasite mised due to drug–drug interactions. For both fanilamide, a sulfonamide derivative [11]. Its Plasmodium falciparum or infections, drugs are taken for a long period (at success in the treatment of bacterial infections Plasmodium vivax in humans. least 6 months for TB, and on a chronic basis led to the synthesis of several sulfonamide and Tuberculosis (TB): Human for HIV), and some drugs have severe drug– sulfone derivatives, which were investigated disease caused by the drug interactions. For instance, rifampicin, a for their potential to treat other infectious dis- mycobacterium agent potent cytochrome P450 3A4 enzyme inducer, eases, including malaria. These compounds Mycobacterium tuberculosis. increases the metabolism of protease inhibi- are analogs of para-amino-benzoic acid, and Antimalarial: Chemical tors, thus diminishing the effectiveness of this therefore block the action of dihydropteroate entities that kill, block or prevent the multiplication of the important class of HIV drugs. Consequently, synthase (DHPS), the enzyme that condenses malaria parasite. rifampicin should not be used when patients are para-amino-benzoic acid with pterin to generate Anti-TB: Chemical entities that on HIV treatment containing protease inhibi- dihydropteroate. The addition of glutamate to kill, block or prevent the tors. To overcome this limitation, analogs of the latter gives rise to dihydrofolate, which is multiplication of rifampicin with a reduced effect on cytochrome then reduced to tetrahydrofolate by dihydrofo- Mycobacterium tuberculosis. P450, such as rifabutin, have been introduced late reductase (DHFR) [12]. This de novo folate Drug repositioning: Finding in lieu of rifampicin. Unfortunately, safe and synthesis pathway exists both in bacteria and new therapeutic uses of old and effective doses of this agent have yet to be estab- the malaria parasite. existing drugs. lished. Thus, new anti-TB drugs are needed that The sulfonamide drugs sulfanilamide and do not interact with anti-HIV drugs. sulfadiazine, as well as the sulfone dapsone, One of the strategies to discover new therapies were among the first sulfa drugs to be used against certain diseases is to reposition, repur- to treat malaria infections [12]. Their use was pose or find new uses for drugs that are already abandoned because of their low efficacy and used for other indications. This approach, unacceptable toxicity. However, renewed inter- which has the advantage of reducing the cost est in this class of antifolates was fostered when and shortening the time of drug development, it was demonstrated that they synergized with has become an important area of research by the inhibitors of DHFR, thus explaining their use pharmaceutical industry [9,10]. For instance, in as components in antifolate combinations. 2004, almost 40% of drugs registered by the US The sulfonamide sulfadoxine has been com- FDA found new uses in the treatment of various bined with the DHFR inhibitor pyrimethamine ® conditions in humans [9]. (PM) under the name of Fansidar . This drug Drug repositioning has previously been had been extensively used as a first-line treat- exploited in the treatment of malaria and TB. ment for uncomplicated malaria replacing chlo- Indeed, some drugs that are, or have been, cen- roquine (CQ). However, this combination is tral in malaria and TB treatment were initially no longer used for mass treatment because of developed for the treatment of non-malaria or widespread resistance [12], although it is still of TB diseases. In this review, we discuss work value in intermittent preventive treatment in that has led to the discovery and develop- pregnancy (IPTP) [13]. Another sulfonamide, ment of such antimalarials and anti-TB drugs, sulfalene, and the sulfone dapsone have also and propose strategies to discover new uses been combined with PM, under the names for old drugs. We have limited our review to Metakelfin® and Malorprim®, respectively. drugs that have reached advanced preclinical However, they have not been used as widely stages (animal models) or clinical development as Fansidar [12]. Recently, dapsone has been in human. developed in combination with chlorproguanil, which is converted to the inhibitor of DHFR Repositioning in malaria chlorcycloguanil in vivo, to treat Fansidar- Antibacterial sulfonamides & sulfones resistant parasites. Unfortunately, this combi- The first drugs to be repositioned for the treat- nation has been withdrawn because of toxicity ment of malaria were