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Review Special Focus: Neglected Diseases

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Drug repositioning in the treatment of and TB

The emergence and spread of in the malaria parasite 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 derivatives, drugs that form the backbone of antimalarial . 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 , , 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 – period, posing the challenge of compliance. In 24th Floor, NY 10005, USA †Author for correspondence: being the first ACT to be intro- addition, the development and spread of multi- E-mail: [email protected] duced into Africa [2]. / drug-resistant strains of Mycobacterium tubercu� and / 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., , kanamycin or (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 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 [11]. is a , which is patients co-infected with HIV is often compro- converted in vivo to the active compound sul- Malaria: Disease caused by a (apicomplexa) parasite mised due to drug–drug interactions. For both fanilamide, a derivative [11]. Its or infections, drugs are taken for a long period (at success in the treatment of bacterial infections 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 3A4 enzyme inducer, eases, including malaria. These compounds Mycobacterium tuberculosis. increases the 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 , 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 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 and do not interact with anti-HIV drugs. , as well as the sulfone , 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 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 [9,10]. For instance, in as components in combinations. 2004, almost 40% of drugs registered by the US The sulfonamide has been com- FDA found new uses in the treatment of various bined with the DHFR inhibitor ® 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- (IPTP) [13]. Another sulfonamide, ment of such antimalarials and anti-TB drugs, , 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 , 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 the sulfur-based anti- associated with dapsone [14]. Thus, sulfa-based bacterial drugs. These drugs were developed drugs, initially developed as antibacterial in the early 1900s as industrial azo-dyes. The agents, have been central in the development of discovery that some of these compounds pos- antifolate-based combinations against malaria. sessed antibacterial activity led to the develop- The chemical structures of sulfadoxine and dap- ment of Prontosil, the first drug ever discov- sone, along with other repositioned drugs are ered that could treat a wide range of bacterial given in Figure 1.

1414 Future Med. Chem. (2011) 3(11) future science group Drug repositioning in the treatment of malaria & TB | Review

„„Antibacterial O N N O O N / O O S O O S S N OMe N In the past, attempts were made to use H H OMe ® H2N NH2 [15] H2N Co-trimoxazole , the antibacterial combina- H2N tion of trimethoprim, a potent inhibitor of the Sulfadoxine Dapsone Sulfamethoxazole bacterial DHFR, and sulfamethoxazole, inhibi- tor of DHPS, for the treatment of malaria infec- OMe NO2 MeO N NH O O O tions. This drug has also been shown to treat 2 S H O P N malaria infection [16,17], and, in some studies, it N 2 3 N MeO N was reported to be as efficacious as Fansidar [18]. OH NH Unfortunately, Fansidar-resistant parasites are also 2 resistant to Co-trimoxazole, which, as a result, Trimethoprim Fosmidomycin did not present any advantage over Fansidar [19]. N N NH2 Recently, this drug has been evaluated in OH NMe H H 2 N N combination with artemisinin derivatives [20]. N OH H Co-trimoxazole has been recommended by N NH HO2C 2 NH2 the WHO for the treatment of childhood febrile OH O OH O OH O O diseases and for prophylaxis against opportunistic HO O infections in HIV-infected patients in Africa [21]. Methotrexate This use as a prophylactic agent has been asso- ciated with a reduction in malaria incidents Figure 1. Selected drugs that have been repositioned for the treatment in many parts of Africa [20] in areas of low to of malaria. moderate Fansidar resistance. Thus, the use of Co-trimoxazole as an antibacterial prophylactic agent can also prevent the incidence of malaria. cancer, and this dose can yield serum concentra- The long safety history of Co-trimoxazole tions of >1000 µM, the range of concentrations when used in pregnancy (to treat bacterial infec- that is associated with MTX’s life threatening tions) and its antimalarial prophylactic properties toxicity [24]. On the other hand, a 1000-fold have led to the evaluation of this combination lower dose of MTX (LD-MTX) (0.1–0.35 mg/kg in the prevention of malaria in pregnancy. This [7.5–25 mg per adult]) has been used once weekly combination is now part of the Medicines for in the treatment of rheumatoid arthritis (RA) on Malaria Venture portfolio, and clinical trials are a chronic basis for many years. At this dose, MTX currently under way to evaluate its prophylactic is safe and remains the mainstay in the treatment properties in pregnancy [203]. of RA in the western world [25]. LD-MTX is also the drug of choice for the treatment of juvenile „„The anticancer antifolates: methotrexate idiopathic arthritis in children (including infants Cancer and malaria parasite cells are both rapidly of less than 1 year old), a common rheumatic dividing cells. Thus, some of the critical path- disease in the western world [26]. ways that control cell division can be inhibited by The LD-MTX is now considered to be one the same compounds. The proof of this concept of the safest drugs used in the treatment of RA was provided in the 1970s, when methotrexate and its safety profile has led to its new reposi- (MTX), an anticancer drug that disrupts folate tioning in the treatment of various conditions, metabolism, was shown to block malaria parasite including multiple sclerosis [27], inflammatory growth in vivo (Figure 1). A of MTX bowel disease [28], urticaria [29], chronic choles- at 2.5 mg/day for 5 days indicated that this drug tatic disorder [30], Wegener’s granulomatosis [31], was safe and efficacious to treat malaria infec- primary biliary cirrhosis [32] and systemic tion [22,23]. However, these results have never been erythematosus [33], among others. exploited because of concerns over MTX toxicity. Taken together, this information has led us Indeed, at the time these trials were carried out, to revisit the potential of LD-MTX in the treat- MTX was only used in the treatment of cancer, ment of malaria. Our group and others have where it was known to be toxic since it was used demonstrated that MTX is potent against both at high doses. PM-sensitive and resistant laboratory strains and Methotrexate is used at high doses of up to field isolates, including those carrying the Ileu- 5000–12,000 mg/m2/week (130–300 mg/ 164-Leu dhfr codon (the most PM-resistant par- kg/week) for several weeks in the treatment of asite) [34], with IC90/99 values (drug concentration

future science group www.future-science.com 1415 Review | Nzila, Ma & Chibale

Key Term that kills 90 to 99% of parasitemia) of 250 to However, the spread of CQ resistance coupled 450 nM, values within the range of concen- with the need to develop new antimalarials led Multidrug resistance: Refers to the inability of an trations achieved in vivo when LD-MTX is to a renewed interest in these . The antimalarial or anti-TB drug to used [35,36]. We have carried out a Phase I evalu- first use of these antibiotics was in the preven- kill, block or prevent the ation of LD-MTX in 25 healthy male volun- tion of malaria. (doxycycline and multiplication of malaria or Mycobacterium tuberculosis. teers, as a step towards its development as an ) are commonly used as antima- antimalarial (NCT00791531 [204]). The results larial prophylactic agents, mainly in Southeast from this trial demonstrate that 2.5 mg/day for Asia, an area where multidrug resistance is 5 days is safe, although the in vivo achieved prevalent [42]. concentration is below 400 nM [37]. Thus, an Antibiotics such as the lincosamide, clinda- evaluation of 5 mg/day for 3 days (instead of mycin; the macrolide, ; and eryth- 5 days) would yield sufficient MTX concentra- romycin have been evaluated in the treatment of tion to clear malaria infection. Thus, the poten- malaria. Although in some studies cures tial exists for this anticancer drug to become were attained [43], their efficacy overall was lim- an antimalarial. ited, and in addition, as discussed earlier, they are all characterized by a delayed clearance time „„Other antibiotics of parasite as a result of DDE [44,45], an effect also Agents with a long-acting effect associated with delays in fever clearance, making (delayed-death effect) these drugs unattractive for malaria treatment. Early studies using animal models showed the To counterbalance this DDE shortfall, these potential of the antibiotics drugs have been combined with rapid-acting and tetracycline to treat murine malaria [38]. standard antimalarials. CQ or QN have been However, these drugs were slow-acting, requir- combined with azithromycin, or ing up to 1 week to clear malaria infection. [46]. Apart from clindamycin com- This is now known as the ‘delayed-death effect binations, these combinations have been proven (DDE)’, a hallmark of antibiotics such as tet- synergistic , justifying their clinical racycline, doxycycline, clindamycin, erythro- evaluation [47]. Combinations with the antifo- mycin and azithromycin, among others. The lates PM/sulfadoxine (Fansidar) have also been mechanism of the DDE is now well understood. investigated [18]. Although overall, the results These antibiotics target the parasite apicoplast, have been encouraging, none of these combina- a nonphotosynthetic plastid organelle unique tions have reached Phase III/IV, probably due to to apicomplexa parasites. The apicoplast has concerns about resistance to the partner drugs its own genome and expresses a small number CQ, QN or Fansidar. of genes (approximately 30 in total), but the Artemisinin-based combinations of artesu- vast majority of its proteome is encoded in the nate with azithromycin or clindamycin are being nuclear genome. evaluated [46]. However, this concept may be Antibiotics disrupt the apicoplast translation compromised by the emergence of artemisinin machinery during the first replication cycle, resistance [3]. leading to a distribution of nonfunctional api- The safety of some of these antibiotics in coplasts into the progeny. However, during this pregnancy, mainly azithromycin, has led to its first cycle, these antibiotics do not affect the use in combination with CQ in the treatment apicoplast metabolic functions, especially those of pregnant women and, especially in IPTP, as catalyzed by nuclear-encoded proteins, since an alternative to Fansidar [48]. This combination they are already present in the apicoplast at the is now in Phase II/III clinical trials for IPTP time of the antibacterial exposure. This leads to (NCT01103063 [205]) [203]. normal parasite growth during the first cycle. The inhibition of translation machinery during Antibiotics with rapid-acting effects the first cycle leads to disruptions in the import In addition to the aforementioned antibiotics or export of new nuclear and apicoplast-encoded (those associated with DDE), other antibiotics, proteins during the second cycle, resulting in such as fosmidomycin, rifampicin or ciprofloxa- cell death, hence the DDE. We refer readers to cin, also possess antimalarial activities and elim- three excellent reviews on this topic [39–41]. inate parasites more rapidly than short-acting This DDE, which is translated in vivo by the antibiotics. Fosmidomycin is the most potent delayed clearance of the malaria parasite, did rapid-acting against malaria, and its not favor their development as antimalarials. discovery has been the most informative. Indeed,

1416 Future Med. Chem. (2011) 3(11) future science group Drug repositioning in the treatment of malaria & TB | Review the fatty acid precursor isoprene is synthesized Drug repositioning in TB through the ‘mevalonic pathway’ in mamma- Over the last five decades, much effort has been lian and many other cells. However, bacteria dedicated to the discovery and development of cells have an alternative pathway, known as the new antibacterial agents. The discovery of one ‘non-mevalonic pathway’. Fosmidomycin, an agent active against one bacterium species, in inhibitor of one of the critical enzymes of this most cases, leads to the testing of the same agent pathway, deoxy-xylulose 5-phosphate reducto- against other species. This concept is known as isomerase, is a potent antibacterial agent. Using ‘spectrum expansion’, and drugs that suppress the malaria genome information, Jomaa and col- the growth of several different bacteria species leagues discovered that malaria parasites use a have a ‘broad-spectrum activity’. As TB is a ‘non-mevalonic pathway’ to synthesize isoprene, bacterium species, many broad-spectrum agents as bacteria cells do, leading to the discovery of have also been tested against this species. Thus, fosmidomycin as a potent antimalarial both the repositioned drugs in TB are mainly derived in vitro and in vivo [39]. from two approaches: ‘spectrum expansion’ of Because it is rapid-acting, fosmidomycin has antibacterials and the new use of non-antibac- become an ideal partner to be used in combina- terial agents. The chemical structures of some tion with short-acting antibiotics to treat uncom- repositioned drugs are given in Figure 2. plicated malaria. Fosmidomycin and clinda- mycin have been evaluated and have reached „„Spectrum expansion of Phase II/III clinical trials; the combination has antibacterial agents proven efficacious [49], although in one study, Oxazolidinones: linezolid reduced efficacy was observed in younger chil- In the 1980s and 1990s, the emergence and dren (younger than 2 years) [50]. Fosmidomycin spread of resistant Gram-positive bacteria, has also been combined with artemisinin deriva- mainly cocci of the group of methicillin-resistant tives [51]. Clearly, more studies are still needed to Staphylococcus, -resistant enterococci establish the efficacy and effectiveness of these and -resistant Streptococcus pneumoniae fosmidomycin combinations. Cl

The antiprotozoa & antibacterial agent tinidazole N N N Cl Tinidazole is a compound, a N derivative of . Like metronida- Cl N NH zole, tinidazole has been used for the treat- O Cl ment of anaerobic protozoa, including and bacteria. In 1985, James treated a patient with amoeba infection using ; this Cl patient also had a co-infection of malaria Clofazimine Plasmodium vivax, which was cleared in the O F same treatment, leading to the investigation N OH O H H of emetine as an antimalarial. Unfortunately, OH N S O O N because of its toxicity, the anti-amoebic eme- O2N tine was replaced by metronidazole, and studies O CO2H N NMe N indicate that metronidazole could treat P. vivax NHAc H 2 and P. falciparum infections [52]. However, Linezolid Meropenem Metronidazole metronidazole toxicity prevented its further investigation as an antimalarial. Tinidazole, O N a metronidazole derivative, which has a lower F CO2H toxicity profile than metronidazole, has been H HN N N developed, and one trial indicated that this drug N SMe OMe could clear P. vivax infection [53]. Currently, a H Phase II investigation of tinidazole efficacy for S radical cure (including against the hypnozoites Thioridazine or the dormant forms) of P. vivax is being con- ducted by the Walter Reed Army Institute of Figure 2. Selected drugs that have been repositioned for the treatment of TB. Research (NCT00811096 [206]).

future science group www.future-science.com 1417 Review | Nzila, Ma & Chibale

prompted extensive work to discover new anti- activity against the enzyme target, the DNA microbials active against drug-resistant bacteria. gyrase, and improved transport through the bac- This effort led to the discovery of linezolid, an teria cell membrane. (the first fluo- oxazolidinone derivative with broad-spectrum roquinolone) was developed in the 1980s, and activity. The mode of action of this drug stems since then, many fluoroquinolones have been from the inhibition of protein synthesis, and developed and marketed [60]. Several fluoroqui- unlike most known protein synthesis inhibi- nolones have proved to be potent against Mtb, tors, this drug targets the early stage of protein among them, (the first to be tested synthesis [54]. Linezolid was introduced in the against TB in humans), , levoflox- 1990s for the treatment of several types of infec- acin, , and moxifloxa- tions caused by methicillin, vancomycin and cin. Of these, gatifloxacin and moxifloxacin are penicillin-resistant strains [54]. the most active [7,8,61]. Fluoroquinolones have The broad-spectrum activity of linezolid led been widely used as second-line agents for the to the investigation of its potency against TB treatment of MDR-TB. bacteria. In vitro and in vivo investigations in the One of the limitations associated with cur- mouse model indicated that this drug was active rent TB treatment is the lengthy time required or moderately active against TB [55]. The use of for a full treatment course, usually varying from this drug in a small number of patients yielded 6 to 24 months. In vivo studies in mice have encouraging results [56], although low efficacy demonstrated that gatifloxacin and moxifloxacin was also reported [57]. However, its long-term have the potential to shorten the treatment of use in the treatment of TB was associated with drug-sensitive TB from 6 to 4 months [62], and toxicities, mainly severe anemia, peripheral and preliminary clinical studies confirmed similar optic neuropathy [6,8]. Nevertheless, this drug is observations in human when gatifloxacin or currently being evaluated in a Phase I/II trial to moxifloxacin was substituted for ethambutol treat MDR-TB and XDR-TB in South Korea, or isoniazid [63,64]. Further investigations at the Brazil and South Africa (NCT00727844 [207], Phase III stage are under way to establish the full NCT00396084 [208], NCT00691392 [209] and potential of these two new fluoroquinolone-con- NCT00664313 [210]). taining regimens to shorten the treatment dura- PNU-100480, a linezolid analog, is being tion to 4 months. To date, more than 14 clinical evaluated for both drug-sensitive and drug-resis- trials have been conducted for the treatment of tant TB. This compound is slightly more active TB with these two drugs [215]. It is worth noting than linezolid in vitro but significantly more effi- that gatifloxacin has recently been withdrawn cacious in vivo in the mouse model [58,59], and from the market due to safety concerns. has pronounced activity in combination with moxifloxacin and pyrazinamide. Currently, Riminophenazine derivatives: the case two Phase I clinical trials have been completed of clofazimine to evaluate its safety and in The repositioning of clofazimine is one of healthy volunteers (NCT00990990 [211] and the most interesting. Indeed, clofazimine was NCT01225640 [212]) [6,8]. Another oxazolidi- previously synthesized and tested against TB none compound, AZD5847, is also in clinical in vitro [65]. This encouraging result led to its development for TB (NCT01037725 [213] and investigation in vivo, in guinea pig and sim- NCT01116258 [214]). ian (monkey) models of TB. Unfortunately, its in vitro activity did not translate to in vivo efficacy Fluoroquinolone and as a result, the drug was abandoned [65]. The discovery of quinolone (which eventually Although the development of clofazimine for gave rise to fluoroquinolone) resulted from TB was abandoned because of its low efficacy in research aimed at synthesizing analogs of CQ guinea pig and monkey models, the two models as antimalarial agents [60]. Chloroquinolone that were then used for TB. However, careful derivatives proved active against bacteria, and examination of the data indicated that this low further investigations led to the discovery and efficacy was the result of poor oral bioavailabil- development of , the first agent ity of this compound in these two animal spe- from the quinolone class, which was used for cies, indeed good efficacy was reported in mice the treatment of urinary tract infections in the and hamster models [65]. In spite of these find- 1960s [60]. The insertion of a fluorine atom to ings, there was no interest in clofazimine, until the 6-position of quinolone resulted in increased its potential against Mycobacterium leprae, the

1418 Future Med. Chem. (2011) 3(11) future science group Drug repositioning in the treatment of malaria & TB | Review pathogen responsible for leprosy was shown by Augmentin™. This combination is now the drug Browne and Hergerhe [66]. This drug was devel- of choice in the treatment of respiratory tract ® oped as Lamprene and marketed for the treat- infections [73]. ment of leprosy [67]. This drug has also been found Several reports have shown the inhibitory to be central in the treatment of infections caused potency of clavulanic acid against the Mtb by bacteria species of Mycobacterium avium b-lactamase, raising a renewed interest in b-lac- complex, responsible for a disseminated form of tam antibiotics [74]. Further studies indicated that infection (not lung infection), and the disease b-lactam antibiotics of the carbapenem family is commonly found in immune-­compromised (especially meropenem and imipenem) and of the conditions, such as HIV infections [68]. cephalosporin family were more active against In addition to its bactericidal effect, this Mtb in vitro than penicillin derivatives [74,75]. The compound also has anti-inflammatory prop- combination of meropenem–clavulanic acid has erties, leading to its use in non-mycobacterial been proposed as a potential anti-TB agent [76,77]. chronic inflammatory diseases of the skin, such However, clinical evaluation of this combination as lupus erythematosus and pyoderma gan- has yet to be conducted. grenosum, among others [67]. In addition, it has been reported to possess interesting anti-tumor „„Drugs with new indications properties [69]. Phenothiazines: the case of thioridazine One of the issues associated with clofazi- Phenothiazines are drugs with antihistaminic or mine is its extremely long half-life (~70 days in antipsychotic properties. Early studies showed humans), which leads to drug accumulation in the antibacterial activity of , the tissues and skin pigmentation [70]. The emer- first commercially available phenothiazine, which gence of MDR-TB and XDR-TB has led to a could suppress bacteria growth [78]. However, renewed interest in clofazimine. This drug has the serious side effects associated with the use been included in the anti-TB armamentarium of this agent for psychoses reduced interest in its for MDR-TB and XDR-TB treatment, albeit exploration as an agent. its efficacy in humans has yet to be fully estab- The search for new drugs active against lished [6,7]. New and improved analogs, with a MDR-TB has led to a renewed interest in this shorter half-life and than clofazimine without its family of drugs. Indeed, new phenothiazines with skin pigmentation liability, are needed to fully improved toxicity profiles have been developed, capitalize on the potential of this interesting and used in the treatment of psychoses. One of compound class. them, thioridazine, has shown promising activ- ity against MDR-TB and XDR-TB in vitro and b-lactam antibiotics in vivo in a mouse model [79]. Evidence indicates b-lactam antibiotics are derivatives of penicillin, that phenothiazines inhibit NADH:menaquinone cephalosporin and carbapenem and form one oxidoreductase activity, an essential enzyme in of the most important classes of antibacterial the energy metabolism pathway and, therefore, agents. Indeed, b-lactam antibiotics have broad represent a novel mechanism of action [80]. spectrum activity, killing both Gram-negative Thioridazine has demonstrated unique activity and -positive bacteria. against the nonreplicating Mtb cultures grown However, this drug class has not been used under hypoxic conditions [81]. The first-line TB against TB. An early report in the late 1940s indi- drugs rifampicin and pyrazinamide have demon- cated that TB expresses a b-lactamase (penicillin- strated some activity against the nonreplicating ase), an enzyme that degrades the lactam ring of Mtb cultures and are largely responsible for short- the drug, rendering the drug inactive. Subsequent ening TB therapy from 18 months to 6 months. studies confirmed the low activity of penicillin However, the safety and efficacy of thioridazine against TB [71]; as a result, b-lactam antibiotics against TB has yet to be established in clinical were not tested further against TB. trials [82]. The expression of b-lactamase in bacteria has been associated with resistance to b-lactam Nitroimidazole derivatives: metronidazole antibiotics. To overcome this resistance, clavu- These drugs belong to the family, and lanic acid, a potent inhibitor of b-lactamases, are used for the treatment of anaerobic protozoa has been developed. This compound restores and bacterial infections. One of these drugs, tini- b-lactam activity [72], and has been combined dazole, has been repositioned for the treatment with amoxicillin under the trade name of of malaria.

future science group www.future-science.com 1419 Review | Nzila, Ma & Chibale

Mtb responsible for human TB may adopt involves inhibition of the fungus enzyme ‘lanos- various metabolic states. The fast-replicating terol 14 a-demethylase’ (also known as CYP51A1 populations are metabolically active and more and P45014DM). This enzyme leads to the syn- susceptible to drug treatment. The slow-grow- thesis of ergosterol from lanosterol, an important ing or nonreplicating populations are meta- constituent of the fungus cell membrane [88]. bolically inactive or dormant and much harder Using genome information, a homologous gene to kill. Most available drugs are poorly active that encoded for a sterol 14 a-demethylase was against the dormant forms, and these forms identified, raising the hypothesis that azole are likely responsible for long-term treatment compounds could also inhibit TB growth. This and post-therapy relapse. Thus, drugs active hypothesis was later proven by Ahmad et al. who against these dormant forms are needed in the showed that the azole econazole and armamentarium against TB. have anti-TB effects both in vivo Most actively replicating tubercle bacilli and ex vivo, including against MDR-TB [89–91]. die rapidly when they are abruptly deprived However, azoles, in general, have poor oral bio- of oxygen, and few of them shift into a state availability, limiting their use as oral drugs. To of dormancy where they adapt to a gradually overcome this limitation, nanoparticles encapsu- decreasing supply of oxygen. This adaptation lated with an econazole-containing regimen are to an hypoxia environment is one of the main being evaluated, and have reached the animal characteristics of the dormancy state [83]. Other evaluation stage [92], a step towards their devel- parameters, such as the lack of nutrients and opment for potential oral use against MDR-TB the production of nitric oxide, can contrib- and XDR-TB. ute to dormancy [84]. Available information on metronidazole as being selective and effec- How to identify new antimalarial & tive against anaerobes led Wayne and Sramek anti-TB agents from old drugs to test it against TB [83]. The results revealed The aforementioned repositioned drugs were the bactericidal effect of this drug against the discovered using different strategies, which we dormant form of TB, providing a rationale for have summarized below. the use of nitroimidazole derivatives as poten- tial anti-TB agents. Although limited, clinical „„Similarity in cell biology & evaluations of metronidazole in combination biological processes with streptomycin, rifampicin and isoniazid As discussed earlier, several strategies have been have been conducted in human, with encour- used to identify drugs for repositioning. The aging results [85]. Another study evaluating the first is cell biology-based. In this regard, it is potency of a metronidazole-containing regimen noteworthy that bacteria, malaria parasites and to clear MDR-TB has recently been completed cancer cells are rapidly dividing cells, thus drugs in South Korea (NCT00425113 [216]). that target one of these cells could also poten- Two members of a new generation of the tially block the division of the other cell. The nitro-imidazole class are currently under devel- previously mentioned sulfa-drugs as antimalarial opment for the treatment of TB: OPC-67683 agents are excellent examples of this approach. and PA-824 [86]. It is noteworthy that these com- Further investigation demonstrated that sulfa- pounds are that require activation by based drugs target the same enzyme in both bac- mycobacteria, through nitro-reduction. This teria and malaria, the DHPS enzyme. Likewise, process produces multiple, highly reactive spe- MTX, an inhibitor of the mammalian folate cies that have been shown to inhibit lipid (and pathway, also blocks the synthesis of folate in the therefore cell wall) and protein biosynthesis [87]. malaria parasite, highlighting its potential as an These drugs have now reached Phase II clinical antimalarial. In vitro studies have demonstrated trials for the treatment of both drug-sensitive that many other anticancer drugs are endowed and -resistant TB (NCT00685360 [217] and with antimalarial activity, thus could potentially NCT00567840 [218]), and PA-824 is part of the be repositioned to become antimalarial drugs if TB Alliance portfolio [219]. they demonstrate an acceptable safety profile at a dose that can yield sufficient drug concentration Azole drugs: econazole to clear malaria infections. The rationale behind the repositioning of this Another example where similarities in cell drug family is based on exploiting the Mtb biology and/or biological processes in dif- genome. The mechanism of action of azoles ferent organisms could be targeted for drug

1420 Future Med. Chem. (2011) 3(11) future science group Drug repositioning in the treatment of malaria & TB | Review repositioning in malaria is antiretroviral prote- non-mevalonic pathway to synthesize isoprene. ase inhibitors (APIs). Aspartic proteases are also Since fosmidomycin, a drug targeting this path- important in malaria parasites (as plasmepsins), way, had already been developed against bacte- and APIs have been reported to have inhibitory ria, the testing of the same drug led to its dis- effects on the malaria parasite P. falciparum. The covery as an antimalarial. In TB treatment, this APIs saquinavir, , , nelfinavir, approach has been exploited with the discovery amprenavir, lopinavir and atazanavir directly that mycobacteria have a gene that encodes for inhibit erythrocytic stages of P. falciparum grown a sterol 14 a-demethylase, an enzyme that is the in vitro at concentrations achieved in vivo [93,94]. target of azole compounds in fungi. Thus, this Some APIs also seem to exert an effect on the family of drugs could also kill Mtb. One of the pre-erythrocytic stages of the malaria parasite. azoles, econazole, has proven potent against TB. The APIs saquinavir and lopinavir inhibited the Another strategy could explore interactions of development of extra-erythrocytic stages proteins with existing drugs, on a proteome-wide in vitro using Plasmodium berghei, a rodent strain scale, using an integrated chemical and biologi- of malaria. In vivo animal (mouse) studies using cal computational strategies. The binding site the rodent strain Plasmodium yoelii showed a of an existing drug can be predicted from a 3D reduction in liver parasite burden when lopina- structure or model of the target protein, and vir/ritonavir was administered [95]. Thus, APIs using this information, off-targets with similar could be repositioned for use in malaria chemo- ligand-binding sites can be identified across the therapy, with the advantage of being used in proteome using functional site search algorithms. malaria–HIV co-infections. Drugs that give rise to favorable protein­–drug TB and other bacteria species share more than complexes would be good potential candidates 99% of biochemical pathways, thus antibiotics for drug repositioning. This approach has been with broad-spectrum activity are also likely to used recently, and has led to the discovery of be active against Mtb, so long as they are able to entacapone and tolcapone, two drugs used for efficiently cross the mycobacterial cell wall. The the treatment of Parkinson’s disease, as potential use of this approach has led to the discovery of anti-TB drugs [97]. important anti-TB drugs, such as moxifloxacin and gatifloxacin (fluoroquinolone), linezolid „„Revisiting or reconsidering data from the (oxazolidinone), clofazimine (riminophenazine) failed repositioning of drugs and meropenem-clavulanic acid (lactam/lac- Attempts have previously been made to reposi- tamase inhibitor). Other antibiotics, such as the tion many drugs. So far this has met with little macrolide clarithromycin, although not active success due to failures at various stages of the against TB, can synergize with standard anti-TB value chain. The revisiting or reconsideration drugs, such as rifampicin and isoniazid in vitro, of data generated during these studies could raising the possibility of combining macrolides lead to their ‘rediscovery’. For instance, since with anti-TB drugs [96]. However, in vivo studies the 1950s, b-lactam antibiotics have been aban- are still needed to confirm this concept. doned as potential treatments for TB because The existence of similar biological processes the cell expressed b-lactamase (penicillinase), in cells, even phylogenetically far from each the enzyme that degrades these drugs. However, other, can also be exploited. For instance, met- since then, inhibitors of b-lactamase (such as ronidazole is known to be active against anaero- clavulanic acid) have been developed, and com- bic organisms, and it is reasonable to postulate bined with b-lactam antibiotics for clinical use. that the process of dormancy or latency in TB Thus, the same combinations could also be is similar to hypoxia conditions. As already tested against TB; one of these combinations, mentioned, this observation led to the testing meropenem-clavulanic acid has proven active in of metronidazole against TB. preclinical stages [76,77]. Clofazimine was initially discovered as an anti- „„Exploitation of genome information TB agent but it was abandoned for this purpose. Another approach is the use of cell genome Instead, it was developed as an antileprosy agent. information to identify potential drug targets As discussed earlier, it was abandoned because it that have been validated in another organism. was found not to be efficacious in the TB animal For instance, using the malaria genome infor- models that were in use at the time. Subsequent mation, Jomaa and colleagues discovered that studies indicated that the two animal species bacterial and malaria parasites utilize the same used are associated with poor

future science group www.future-science.com 1421 Review | Nzila, Ma & Chibale

of clofazimine, explaining the observed lack of among them the antimalarial , a drug efficacy. Clearly, these previous models were not used to treat the dormant forms (hypnozoites) of appropriate for clofazimine. The potential of malaria [99]. The antimalarial has also this drug class as anti-TB agents has been revis- been discovered to be active against Mtb [100]. ited, and it could become part of the anti-TB This drug is known to have serious neurologi- armamentarium [6,7]. cal side effects; as a result, analogs are being Drugs used in one disease can present high synthesized and tested as potential anti-Mtb risks of toxicity in another disease, and some agents [101–103]. attempts at drug repositioning failed because of the risk of toxicity. However, the development of Conclusion analogs with better safety profiles could lead to The emergence of artemisinin resistance is threat- successful drug repositioning. ening the current concept of ACTs. The spread For instance, the antiprotozoa metronidazole of MDR-TB and XDR-TB is reducing the effec- was abandoned as an antimalarial agent because tiveness of current anti-TB drugs. Therefore, new of its toxicity. However, the development of a drugs are urgently needed. The human pharma- safer analog, tinidazole, to treat protozoa, led copoeia is rich. It is estimated that 12,000 drugs to its testing against malaria. This drug is now have been used in humans. It is, therefore, not undergoing clinical evaluation to treat P. vivax unreasonable to propose that several of these malaria [53]. Another interesting example is with drugs have the necessary pharmacological prop- the phenothiazine chlorpromazine, the antihis- erties to become new anti-TB and/or antima- taminic and antipsychotic agent. Its potential larial drugs. The challenge remains to identify to inhibit bacteria growth was proven in the them. Strategies exist to identify such drugs, 1950s but toxicity prevented its further develop- but the main limitation is human and financial ment [78]. A new phenothiazine, thioridazine, an resources. An excellent opportunity now exists to antipsychotic has been developed, and this drug identify new drugs at a low cost and in a relatively has a better safety profile than chlorpromazine. short time period. However, while new drugs can be identified „„Exploitation of co-infection drug efficacy by drug repositioning, the challenge remains to Drugs can be repositioned by careful observa- discover active drugs against dormant/persister tion of co-infection treatment. Indeed, many tubercle bacilli in TB, and the dormant liver diseases occur as co-infections with malaria and stage parasites (hypnozoites) in malaria. Thus, TB, or malaria and HIV, or HIV and TB, thus drug repositioning is only the first step in finding the treatment of one disease could also clear the new uses of old drugs, subsequent ‘drug evolu- concurrent disease. For instance, the discovery of tion’ (optimization of repositioning drugs in new metronidazole and, later, its analog tinidazole, a applications) should be undertaken afterwards. drug that is now undergoing clinical evaluations These specific unique challenges are critical in against P. vivax, has its origins in studies on the controlling the spread of multidrug resistant TB treatment of the protozoa amoeba in patients and malaria. co-infected with malaria. Future perspective „„Drug-screening studies The selection and spread of resistance to antima- Finally, new therapies could be discovered by larial and anti-TB agents require that new drugs be screening of old and existing drugs against discovered urgently. Drug development is a long malaria parasites and Mtb. Recently, a screening and costly undertaking. Given the lack of market of a library of 1000 known drugs against P. fal� incentives and adequate funding to support drug ciparum in vitro led to the discovery of the anti- development in these areas, drug repositioning is malarial activity of astemizole, an antihistaminic going to become a core strategy in malaria and drug [98]. Pharmacokinetics data indicate that TB drug development. As we discussed, strategies safe and tolerable doses of this drug could yield exist to streamline this process. effective concentrations that could clear malaria infection in vivo, warranting its further evalua- Acknowledgments tion in humans [98]. More recently, a medium We thank Timothy Wells (Medicines for Malaria Venture, throughput screening of a library of 1514 known Switzerland) and Collen Masimirembwa (African Institute drugs using the Alamar Blue assay resulted in the of Biomedical Science and Technology, Zimbabwe) for identification of 17 novel inhibitors of Mtb, and helpful discussions.

1422 Future Med. Chem. (2011) 3(11) future science group Drug repositioning in the treatment of malaria & TB | Review

Executive summary Background: repositioning in malaria & in TB „„Emergence of resistance to artemisinin, the backbone of antimalarial therapy, and the development of multidrug-resistant strains and extensively drug-resistant strains are of great concern. „„New drugs are urgently needed to counterbalance this burgeoning drug-resistance problem. „„One of the strategies to discover new therapies is to reposition, repurpose or find new uses for drugs that are already used for other indications. „„Drug repositioning has already been exploited in the past in the treatment of malaria and TB. For instance, sulfa-based drugs for malaria, and fluoroquinoline for TB were initially developed for the treatment of non-malaria or TB diseases. How to identify new antimalarial & anti-TB agents from old drugs „„Similarities in cell biology and biological processes: a drug that targets one pathway in one organism can also target the same pathway in a different organism. For instance, sulfa-based drugs were discovered as antibacterials but have been used as antimalarials. Likewise, some antibiotics discovered for non-TB infections have been repositioned in TB. „„Exploitation of genome information: the discovery of the non-mevalonic pathway to synthesize isoprene in malaria by genome analysis,­ led to the clinical evaluation of fosmidomycin, a drug developed as an inhibitor of the non-mevalonic pathway in bacteria. Likewise, the exploitation of TB genome indicated that this microorganism encodes for sterol 14 a-demethylase enzyme, the enzyme target of azole compounds in fungal organisms. One of the azoles, econazole, has proven potent against TB. „„Revisiting or reconsidering data from failed repositioning drugs: some drugs failed to be repositioned in TB or malaria because they were deemed to be toxic. However, since then, new analogs have been developed with reduced toxicity, and these analogs could be repositioned. One of the best examples is tinidazole replacing metronidazole (used in amoeba infection) in malaria treatment, or the antihistaminic and antipsychotic chlorpromazine being replaced by thioridazine in the treatment of TB. „„Exploitation of co-infection drug efficacy: drugs can be repositioned by careful observation of co-infection treatment. For instance, the discovery of metronidazole, and later its analog tinidazole, a drug that is now undergoing clinical evaluations against Plasmodium vivax, has its origins in studies on the treatment of the protozoa amoeba in patients co-infected with malaria. „„Drug-screening studies: new therapies could be discovered by in vitro screening of old and existing drugs using high-throughput methods. For instance, screening studies have indicated that the antihistaminic astemizole possesses antimalarial activity, whereas the antimalarial primaquine is a potential anti-TB drug.

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future science group www.future-science.com 1425 Review | Nzila, Ma & Chibale

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1426 Future Med. Chem. (2011) 3(11) future science group