Key Paper Evaluation

10.1517/13543784.14.7.917 © 2005 Ashley Publications Ltd ISSN 1354-3784 917

Ashley Publicationswww.ashley-pub.com

New drugs being developed for the treatment of tuberculosisEvaluation of: ANDRIES K, VERHASSELT P, GUILLEMOUNT J et al.: A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. Science (2005) 307:223-227.JIA L, TOMASZEWSKI JE, HANRANHAN C et al.: Pharmacodynamics and pharmacokinetics of SQ-109, a new diamine-based antitubercular drug. Br. J. Pharmacol. (2005) 144:80-87.

Sheila A DoggrellSchool of Nursing, Auckland University of Technology – Akoranga Campus, Northcote, Auckland, New Zealand

More than one-third of the world is infected with tuberculosis (TB) and5000 people die of TB everyday. Of the many diarylquinolones shown to beeffective at inhibiting the multiple-cycle growth of Mycobacterium tubercu-losis, R-207910 was the most active and was chosen as the lead compound. Inthe non-established infection mouse TB model, a single dose of R-20791050 mg/kg had a bacteriostatic effect, and a bactericidal effect was observedat 100 mg/kg. In the established infection mouse model, treatment wasstarted 12 – 14 days after infection, and when added to the triple therapy ofisoniazid, rifampin and pyrazinamide or substituted for any component ofthe triple therapy, R-207910 increased the effectiveness. As ethambutol ischemically simple, and only has modest potency in treating TB, it was consid-ered to be amenable to optimisation by combinatorial chemistry, and fromthe analogues synthesised that inhibited the growth of M. tuberculosis,SQ-109 was eventually selected as the lead compound for further testing. Infemale mice infected with M. tuberculosis H37Rv by tail-vein injection, treat-ment with SQ-109 25 mg p.o. initiated 20 days later for 5 days/week for4 weeks reduced the counts by 1.87 log units, which was slightly more thanwith ethambutol 100 mg (1.67 log units). These results indicate that excitingnew drugs are under development for the treatment of TB.

Keywords: mouse TB models, Mycobacterium tuberculosis, R-207910, SQ-109, tuberculosis

Expert Opin. Investig. Drugs (2005) 14(7):917-920

1. Introduction

Tuberculosis (TB) is a contagious bacterial infection caused by Mycobacterium tuber-culosis. Although the lungs are primarily involved, infection can spread to otherorgans. Once a candidate for elimination, now more than one-third of the world isinfected with TB and 5000 people die of TB everyday [101]. The main reasons forthis are: the close relationship between TB and HIV/AIDS; the lack of compliancewith the present treatments; and the emergence of drug-resistant TB strains [101].HIV infection is the most potent risk factor for converting latent TB into activetransmissible TB [101]. One-third of AIDS patients have TB, and one-third of mor-talities associated with AIDS are caused by TB [101]. Of the TB patients, ∼ 4% havemulti-drug resistant strains to the most effective drugs, isoniazid and rifampin, andthe main reason for drug resistance is failure to complete treatment [101].

Isoniazid and rifampin were developed in the 1950s and 1960s, and there have beenno major new drugs for TB in the last 40 years [101]. Clearly, there is a need for newdrugs in the treatment of TB, and two such drugs are considered in this evaluation,

1. Introduction

2. R-207910

3. SQ-109

4. Expert opinion

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918 Expert Opin. Investig. Drugs (2005) 14(7)

R-207910 (1-[6-bromo-2-methoxy-quinolin-3-yl]-4-dimethyl-amino-2-napthalen-1-yl-1-phenyl-butan-2-ol, see Section 2)and SQ-109 (N-geranyl-N-[2-adamantyl]ethane-1,2-diamine,see Section 3).

2. R-207910

The paper reporting on the antimycobacterial properties ofthe diarylquinolones [1] is summarised in this section.

2.1 CellularOf the many diarylquinolones shown to be effective at inhib-iting the multiple-cycle growth of M. tuberculosis, R-207910was the most active and chosen as the lead compound(Figure 1). In addition to having a minimum inhibitory con-centration of 0.03 µg/ml against recombinant M. tuberculosisH37Rv, R-207910 was similarly effective against six strains offully susceptible clinical isolates, and in strains resistant to iso-niazid, rifampin, isoniazid and rifampin, isoniazid and strep-tomycin, ethambutol, pyazinamide and fluoroquinolone.R-207910 0.3 µg/ml was effective against M. tuberculosisin vitro, reducing the bacterial load by 3 log units after12 days.

R-207910 was selective for mycobacteria. The proportionof resistant mutants with R-207910 against M. tuberculosiswas similar to rifampin-resistant mutants. These R-207910-resistant strains were still susceptible to isoniazid, rifampinand streptomycin. Mutation studies were used to show thatR-207910 inhibits the proton pump of M. tuberculosisATP synthase.

2.2 Mouse studiesIn male mice, R-207910 25 mg/kg was rapidly absorbedwith a maximum plasma concentration of ∼ 1.3 µg/mlwithin 2 – 4 h. R-207910 was distributed to tissues includ-ing the lung and spleen, and there was a long plasma half-life of 44 – 64 h. There was no accumulation in tissues after5 days of oral administration. A dose of 100 mg/kg/day wasable to keep the plasma levels of R-207910 > 0.3 µg/mlthroughout the 24-h period.

In the non-established infection mouse TB model, micewere intravenously infected with M. tuberculosis H37Rv, andthe following day, some started treatment with R-207910 for≤ 28 days. A single dose of R-207910 50 mg/kg had abacteriostatic effect (decreased the bacterial load in the lungsby 0.5 log units) and a bactericidal effect (decrease of≤ 2.5 log units in bacterial load) was observed at 100 mg/kg.Over 4 weeks of treatment with R-207910, the minimal dose(5 days/week) that prevented mortality was 1.5 mg/kg, andthe minimal effective dose at preventing lung lesions was6.5 mg/kg. At 25 mg/kg, R-207910 was more active thanisoniazid as a bactericidal agent.

In the established infection mouse model, treatment wasstarted 12 – 14 days after infection. In this model, R-20791025 mg/kg monotherapy was as effective as triple-combination

therapy with isoniazid, rifampin and pyrazinamide. However,R-207910 is unlikely to be used as monotherapy as this wouldlead to the development of resistance. When added to the tri-ple therapy or substituted for any component of the tripletherapy, R-207910 increased the effectiveness. After 2 monthsof treatment with R-207910, isoniazid and pyrazinamide, orR-207910, isoniazid and rifampin, the lungs of the animalswere culture negative.

2.3 Human studiesNo details are given but it is stated that preclinical safetyassessment in rats and dogs supported the administration ofR-207910 to humans. In healthy humans, after single oraladministration, R-207910 700 mg was readily absorbed withpeak plasma levels approaching 10 µg/ml at 5 h and remained> 0.1 µg/ml for 120 h. There was no excess of adverse effectsover placebo in the 36 subjects with R-207910.

2.4 DiscussionThe mechanism of action of R-207910 is different from otheranti-TB agents, which allows an additive effect when usedwith other anti-TB agents. As the ATP synthases of bacteriaand eukaryotic cells are different, R-207910 is unlikely tohave any adverse effects to humans related to this mechanism.

The authors conclude that conducting clinical developmentin patients with active pulmonary TB is highly warranted.

3. SQ-109

3.1 IntroductionEthambutol or streptomycin with isoniazid, rifampin andpyrazinamide are the standard combination first-line therapyfor M. tuberculosis. As ethambutol is chemically simple(Figure 2) and only has modest potency, it was considered tobe amenable to optimisation by combinatorial chemistry. Atotal of 63,238 diamine analogues of ethambutol were synthe-sised [2], and from the agents that inhibited the growth ofM. tuberculosis, SQ-109 (Figure 2) was eventually selected asthe lead compound for further testing, and the paperdescribing this testing [3] is precised in this section.

3.2 In vitro studiesMouse macrophage RAW264.7 cells were infected withM. tuberculosis H37Rv. The level of infection was measuredfrom relative luminescence units of the luciferase reporterconstruct pSMT1 added to M. tuberculosis. In this assay, theminimal inhibitor concentration (concentration required toproduce 90% inhibition) of 1.56 µM for SQ-109 was slightlyhigher than that of isoniazid (0.73 µM), but lower than thatof ethambutol (24.5 µM).

3.3 In vivo studiesFemale mice were infected with M. tuberculosis H37Rv bytail-vein injection, and oral treatment with SQ-109 (0.1, 10and 25 mg/kg), isoniazid (25 mg/kg) or ethambutol

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Doggrell

Expert Opin. Investig. Drugs (2005) 14(7) 919

(100 mg/kg) was initiated 20 days later for 5 days/week for4 weeks. The three drugs had similar effects on the bacterialconcentrations in the lung and spleen. In the lung, SQ-10925 mg reduced the counts by 1.87 log units, which was lessthan the reduction with isoniazid 25 mg (2.81 log units) butslightly more than with ethambutol 100 mg (1.67 log units).The highest concentrations of SQ-109 were in the lung andspleen, where there was some accumulation with time, andthe concentrations were 10-fold above its minimuminhibitory concentration.

Pharmacokinetic studies with SQ-109 25 mg/kg in miceshowed low oral bioavailability (4%), a maximum plasmaconcentration of 0.14 µg/ml (below the minimum inhibitoryconcentration), a large volume of distribution and an elimina-tion half-life of 5.2 h. As the tissue concentrations are higherthan the plasma concentration, this suggests that SQ-109 rap-idly penetrates into the extravascular compartment. SQ-109was shown to accumulate mostly in the lung and spleen. Lev-els of unchanged SQ-109 excreted in urine and faeces were0.01 and 2% of the dose, respectively.

There were no noticeable side effects with SQ-109; injec-tion site irritation, inability to move, ruffled fur, ataxia, trem-ors, convulsions, emesis, diarrhoea, laboured breathing oracute death.

3.4 DiscussionThe authors point out that the low oral bioavailability ofSQ-109 should not be a problem, especially as it accumulates inits target tissues.

4. Expert opinion

4.1 Other new drugs for tuberculosisThere are other drugs being developed to treat TB. Forinstance, the oxazolidinone linezolid was developed as anantibiotic with good activity against some Gram-positivebacteria including some resistant bacteria. Linezolid also hadhigh activity against isolates of M. tuberculosis [4]. Anotheroxazolidinone compound, PNU-100480 (U-100480), hasalso been shown to be effective after oral administration

against M. tuberculosis [5]. Recently, some analogues ofPNU-100480 have been shown to have activity againstM. tuberculosis in vitro [6]. These oxazolidinones inhibittranslation of the initiation phase of bacterial protein synthe-sis by selectively inhibiting ribosomal peptidyltransferase [6].Thus, it seems that for the first time in many decades there isprogress towards new drugs for TB.

4.2 Mechanism of actionThe different mechanisms of action of the present TB drugscontribute to their ability in combination to give additivebeneficial effects and prevent the development of resistance.Isoniazid inhibits the biosynthesis of mycolic acids (importantconstituents of the mycobacterial cell wall) probably by tar-geting the enoyl-acyl carrier protein reductase of fatty acidsynthase II. Rifampin inhibits the DNA-dependent RNApolymerase of mycobacteria. Ethambutol blocks the arabino-syl transferases involved in cell-wall biosynthesis. Streptomy-cin inhibits protein synthesis by causing misreading and thepremature termination of translation of mRNA. Pyrazina-mide seems to target the mycobacterial fatty acid synthase Igene. With R-207910, there is the introduction of anothermechanism of action for a TB drug; namely, the inhibition ofthe proton pump of M. tuberculosis ATP synthase. This is veryimportant as it gives further possibilities for good therapeuticcombinations of drugs to treat TB as described in the animalstudies [1].

4.3 CongratulationsIt has been 40 years since new drugs have been developed forthe treatment of TB. Initially, this was probably mainlybecause there was not a major need. Subsequently, as the needincreased with the re-emergence of TB, especially in develop-ing countries, economical factors may have hindered thedevelopment of further drugs. R-207910 is being developedby Johnson & Johnson, and SQ-109 by Sequella withresearchers at the National Cancer Institute. Congratulationsare extended to these companies for having the foresight andexpertise to become involved in the development of newdrugs for the treatment of TB.

Figure 1. Chemical structure of R-207910.

R-207910

N

ON

H

Br

O

Figure 2. Chemical structure of ethambutol and SQ-109.

SQ-109

NH

NH

NH

NH

OH

OH

Ethambutol

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920 Expert Opin. Investig. Drugs (2005) 14(7)

Bibliography1. ANDRIES K, VERHASSELT P,

GUILLEMOUNT J et al.: A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. Science (2005) 307: 223-227.

2. LEE RE, PROTOPOPOVA M, CROOKS E et al.: Combinatorial lead optimization of [1,2]-diamines bases on ethambutol as potential antituberculosis preclinical candidates. J. Comb. Chem. (2003) 5:172-187.

3. JIA L, TOMASZEWSKI JE, HANRANHAN C et al.: Pharmacodynamics and pharmacokinetics of SQ-109, a new diamine-based

antitubercular drug. Br. J. Pharmacol. (2005) 144:80-87.

4. ALCALÁ L, RUIZ-SERRANO MJ, TURÉGANO CP-F et al.: In vitro activities of linezolid against clinical isolates of Mycobacterium tuberculosis that are susceptible or resistant to first-line antituberculous drugs. Antimicrob. Agents Chemother. (2003) 47:416-417.

5. BARBACHYN MR, HUTCHINSON DK, BRICKNER SJ et al.: Identification of a novel oxazolidinone (U-100480) with potent antimycobacterial activity. J. Med. Chem. (1996) 39:680-685.

6. SBARDELLA G, MAI A, ARTICO M et al.: Synthesis and in vitro

antimycobacterial activity of novel 3-(1H-pyrrol-1-yl)-2-oxazolidinone analogues of PNU-100480. Bioorg. Med. Chem. Lett. (2004) 14:1537-1541.

Website101. http://www.tballiance/org

TB Alliance website.

AffiliationSheila A Doggrell PhD DScSchool of Nursing, Auckland University of Technology – Akoranga Campus, Northcote, Auckland, New ZealandE-mail: s_doggrell@yahoo.com

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