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REVIEW
Study of clinically used and recently developedantimycobacterial agents
Mohammad Asif
Received: 7 February 2011 /Accepted: 5 April 2011 /Published online: 1 December 2011# Institute of Oriental Medicine, Kyung Hee University 2011
Abstract Tuberculosis is one of most pervasive, respiratorytransmitted diseases and has spread to every corner of theglobe. According World Health Organization report, as muchas one-third of the world’s population is currently infected bytuberculosis. There has been considerable interest in thecurrently used antimycotubercular compounds to inhibit orprevent mycobacterium species. These mycobacterium spe-cies have developed resistant against currently used drugs andproduced toxic effect on long duration of therapy. Theseagents have different structure and almost all compoundshaving heterocyclic ring having one and more than oneheteroatoms. These observations have been guiding for thecurrently used and newly developed antitubercular agents thatpossess potent antimicrobial activity and their side effects,activity against multi drug resistance MDR, XDR mycobac-terium, and also in patient co-infected with HIV/AIDS.
Keywords Antitubercular agents .Mycobacterium .
Multi drug resistance . Side effects . Co-infection
Introduction
Infectious diseases caused by microbes have increaseddramatically in recent years. In spite of many significant
advances in antibacterial therapy, the widespread use andmisuse of antibiotics have caused the emergence of bacterialresistance to antibiotics, which is a serious threat to publichealth. In particular, the emergence of multidrug resistantgram-positive bacteria, including methicillin-resistant Staph-ylococcus aureus (MRSA), vancomycin-resistant S. aureus(VRSA), and vancomycin-resistant Enterococci (VRE), hasbecome a serious problem in the treatment of bacterialdiseases (Islam et al. 2008; Deniz et al. 2008; Mayekar et al.2010; Surendra et al. 2010).
Therefore, the development of new compounds todeal with resistant bacteria has become one of the mostimportant areas of antibacterial research today. Inaddition to the development of new and effectiveantibacterial agents against multidrug resistant grampositive bacteria, recently attention has focused on thetreatment of tuberculosis (TB). Therefore, recent effortshave been directed toward exploring currently used andnewly developed antimycobacterial agents and theirtoxicities and mechanisms (Mayekar et al. 2010; Sure-ndra et al. 2010; Okada and Kobayashi 2000).
Tuberculosis an overview
Tuberculosis (TB) is one of the oldest and most pervasive,respiratory transmitted diseases in history. According WorldHealth Organization (WHO) report, TB has spread to everycorner of the globe. As much as one-third of the world’spopulation is currently infected, more than any otherinfectious disease and the estimated 8.8 million new cases
M. Asif (*)Department of Pharmacy, Guru Ram Das (Post Graduate)Institute of Management and Technology,214-Rajpur road,Dehradun 248009 Uttrakhand, Indiae-mail: [email protected]
Orient Pharm Exp Med (2012) 12:15–34DOI 10.1007/s13596-011-0020-8
every year correspond to 52,000 deaths per week or morethan 7,000 each day(Okada and Kobayashi 2000). Thesenumbers however, are only a partial depiction of the globalTB threat. It was estimated that nearly 1 billion morepeople will be infected with TB in the next 20 years. About15% of that group (150 million) will exhibit symptoms ofthe disease, and about 3.6% (36 million) will die from TB ifnew disease prevention and treatment measures are notdeveloped. However, the total number of new TB cases isstill rising slowly, 95% occur in developing countries everyyear and approximately one million young women per yearare victimized with this disease in the developing world, inthe African, Eastern Mediterranean and South-East Asiaregions (World Health Organisation, Tuberculosis, FactSheet No. 104 2007). The occurrence of this disease islinked to dense population, poor nutrition, and poorsanitation (Dony et al. 2004). Observed Treatment, short-course (DOTS) strategy, constitutes the cornerstone of thecurrent protocol for control of TB. However, the three keydrugs, isoniazide, pyrazinamide and rifampicin, used in theregimen are potentially hepatotoxic and may lead to drugassociated hepatitis. Despite the undoubted success ofDOTS strategy, the emergence of multi drug resistantstrains, recurrently isolated from patient’s sputum, darkenthe future (Omar and Ahmed 2008). The increase in TBincidence during recent years is largely due to theprevalence of TB is synergy with Human Immunodeficien-cy Virus (HIV) epidemic, which augments the risk ofdeveloping the disease 100-fold where 31% of new TBcases were attributable to HIV co-infection, and also theemergence of multidrug resistant tuberculosis (MDR-TB)strains (Elsayed et al. 2000). The treatment of MDR-TB hasbecome a major concern worldwide. In addition to this, theincrease in M. tuberculosis strains resistant to front lineantimycobacterial drugs such as rifampin and INH hasfurther complicated the problem, which clearly indicates theneed for more effective drugs for the efficient managementof tuberculosis (Management of MDR-TB 2009).
The currently available key medications (first line)used in the regimen are show serious side effects likesevere damage to the eighth cranial nerve, inducingirreversible impairment of auditory function, hypersensi-tivity reactions (streptomycin), potentially hepatotoxicand may lead to drug associated hepatitis isoniazide,pyrazinamide and rifampicin (rifampicin, rifabutin, rifa-pentine) and thrombocytopenic purpura (rifampicin)Omar A and Ahmed MA (2008; Kamal et al. 2008).
Second line anti-tb drugs are more toxic than firstline drugs, amikacin and kanamycin causes kidneydamage as well as hearing loss, viomycin and capreo-mycin causes nephrotoxicity and eighth cranial nerve
toxicity. Fluoroquinolones (ciprofloxacin, moxifloxacin,ofloxacin (levofloxacin, the chiral form of ofloxacin ismore effective), gatifloxacin, trovafloxacin, enofloxacinand sparfloxacin etc.). Fluoroquinolones are increasinglycontraindicated for patients due to growing prevalenceof antibiotic resistance. Ethionamid and prothionamide(structural analogues of isoniazid) causes adverse effectsare g.i.t. disorders (such as anorexia, salivation, nausea,abdominal pain, and diarrhea), diverse mental disturban-ces (such as depression, anxiety psychosis, dizziness,drowsiness, and headache) and hypersensitivity. Cyclo-serine causes side effects of this drug are mainly CNSmanifestations such as headache, irritability, depression,convulsions. Para amino salicyclic acid causes g.i.t.problems including anorexia, nausea, epigastric pain,abdominal distress, and diarrhea, peptic ulcers andhypersensitivity reactions (Kamal et al. 2008; Da Silvaet al. 2003; Rieder et al. 2001).
Tuberculosis (TB) is a chronic infectious diseasecaused by mycobacteria of the “tuberculosis complex”,including primarily Mycobacterium tuberculosis, thatdivides every 16 to 20 h, an extremely slow rate comparedwith other bacteria, which usually divide in less than anhour, but also M. bovis and M. africanum, M. canetti, andM. microti can also cause tuberculosis, but these speciesdo not usually infect healthy adults. Tuberculosis, anairborne communicable disease caused by transmission ofaerosolized droplets of M. tuberculosis. The primarysource of infection is viable tubercular bacilli, expelledin the environment by a patient with active TB (Kamal etal. 2008). Mycobacterium is a genus of bacteria, whichgrows slowly under aerobic conditions and is distin-guished by acid-fast staining. They are Gram positive,non-motile, rod-shaped, obligate aerobic bacteria thatbelong to the order actinomycetales, family Mycobacter-iaceae. Several species, including M. tuberculosis, M.bovis, M. africanum, M. microti, M. canetti, M. kansasii,M. avium, and M. leprae, are intracellular pathogens ofhigher vertebrates.
The M. tuberculosis complex includes three other TB-causing mycobacteria: M. bovis, M. africanum and M.microti. The first two only very rarely cause disease inimmuno competent people. On the other hand although M.microti is not usually pathogenic, it is possible that theprevalence of M. microti infections has been underestimated. Other Known pathogenic mycobacteria includeM. leprae, M. avium and M. kansasii. The last two are partof the non tuberculous mycobacterium (NTM) group. Nontuberculous mycobacteria cause neither TB nor leprosy, butthey do cause pulmonary diseases resembling TB. TBrequires much longer periods of treatment to entirely
16 M. Asif
eliminate mycobacteria from the body (Shafii et al. 2008;Nagarajan et al. 2008).
The cell wall of Mycobacterium species in its fullstructural and functional integrity is essential for its growthand survival in the infected host. M. tuberculosis possesses acell wall dominated by covalently linked mycolic acids,arabinogalactan and peptidoglycan (AGP), the mycolic acidsof which are complimented by glycolipids such as α, α-trehalose monomycolate (TMM). This mycolic acid basedpermeability barrier shields the organism from environmen-tal stress and contributes to disease persistence and therefractoriness of M. tuberculosis to many antibiotics (Donyet al. 2004; Kamal et al. 2008).
Unique problems associated with mycobacteria
& Complex outer membrane of mycobacteria.
& Very slow growingThey are intracellular bacteria
& ability to colonize macrophages–in the lung, the M.tuberculosis cell (the tubercle bacilli) is engulfed by amacrophage, which encloses the bacteria into thephagosome compartment.
Typically, the phagosome fuses with the lysozome whichcontains degradative enzymes, low pH, reactive oxygenspecies, etc., to destroy foreign particles. The fusion oftendoes not occur with M. tuberculosis and the bacteriumsurvives in the very cell designed to kill it. As thebacterium multiplies, it kills the macrophage, releasingmore bacteria to be taken up by more macrophages. After~2–3 weeks, other macrophages and T-cells are recruited tothe site and congregate around the infected cells
& ability to remain quiescent for decades& toxicity of effective drugs& poor patient compliance& resistance is widespread
Arrangement of Structural Components in the CellEnvelope of M. tuberculosis, Showing Possible Interactionof Methyl-Branched Long-Chain Components with aMycolic Acid Matrix. Mycolyl arabinogalactan (mAG) isconnected by a phosphoryl linker unit to peptidoglycan (PG).Complex free lipids interact with mAG. Lipoarabinomannan(LAM) and phosphatidylinositol pentamannoside (PIM5) areshown anchored in the plasma membrane (Fig. 1).
Tuberculosis-HIV combination
The current estimations reveal that one-third of the 42million people living with HIV/AIDS worldwide are co-
infected with TB (World Health Organization. Strategicframework to decrease the burden of TB/HIV documents2002). As per WHO reports, approximately 90% of thepatients having both TB and HIV died within a few monthsafter clinical symptoms. Therefore, WHO warned the worldfor “even greater TB-HIV crisis” and called for wideavailability of free anti-TB drugs to those living with HIV.As per WHO, HIV is spreading rapidly in India with thelargest number of TB cases in the world (Espinal 2003;Amalio and Michael 2000).
Drug-resistant tuberculosis
Drug resistance displayed by M. tuberculosis is animportant obstacle for the treatment and control of TB.This resistance has traditionally been attributed to theunusual multi-layer cell envelope and active multidrugefflux pumps. Recent insights into mechanisms thatneutralize the toxicity of antibiotics in the cytoplasm haverevealed other systems that function in synergy with thepermeability barrier and efflux systems to provide naturalresistance. Drugs inhibiting these intrinsic systems wouldenable many antibiotics, which are already available buthave not been used for TB, to gain new activities against M.tuberculosis (Kamal et al. 2008).
Multi drugs resistance-tuberculosis
Multi drugs resistance (MDR) TB refers to simultaneousresistance to at least two or more of the five first-line anti-TBdrugs (isoniazid, rifampicin, pyrazinamide, ethambutol, andstreptomycin) (Barry et al. 2000). Multi-drug-resistance arisesfrom sharing of genes between different species or genera,generally mediated by small pieces of extra-chromosomalDNA known as transposons or plasmids. Treatment formultidrug-resistant tuberculosis is long lasting, less effective,
Fig. 1 Structure of mycobactrium cell membrane
Study of antitubercular agents 17
costly, and poorly tolerated (Global Tuberculosis Control2008).
Extensively drug resistant tuberculosis
Extensively drug resistant (XDR) tuberculosis by defi-nition is resistance to at least isoniazid and rifampicin inaddition to any quinolone and at least one injectablesecond-line agent (any fluoroquinolone, capreomycin,amikacin, kanamycin). The principles of treatment forMDR-TB and XDR-TB are the same. The maindifference is that XDR-TB is associated with a muchhigher mortality rate than MDR-TB, because of reducednumber of effective treatment options. Hence there is anurgent need for novel drugs that are active against M.tuberculosis in order to shorten the duration of tuberculo-sis therapy (Kamal et al. 2008).
Materials and methods
Chemotherapy of tuberculosis
(a) First Line Anti-Tubercular Agents
Chemotherapy of TB are mainly depends on first-lineantitubercular drugs (Fig. 2), which include streptomycin(SM), isoniazid (INH), rifampicin (RMP), ethambutol(EMB) and pyrazinamide (PZA), they more effective andless toxic as compare to second-line antitubercular drugs(Kamal et al. 2008).
(b) Second Line Anti-Tb Drugs
According to WHO there are six classes of second linedrugs that are used in the treatment of tuberculosis (Centerfor Disease Control (Center for Disease Control 2006)). Adrug may be classified as a second-line because of one oftwo possible reasons: 1) it may be less effective than thefirst-line drugs or it may have toxic side-effects or 2). Thesecomprise of different classes namely, aminoglycosides(Fig. 3): (amikacin, kanamycin), polypeptides: (capreomy-cin, viomycin), fluoroquinolones (Fig. 4): (ciprofloxacin,moxifloxacin, etc.), thioamides: (ethionamides, prothioa-mide), cycloserine and p-aminosalicylic acid (Fig. 5).
Drugs for HIV/TB
Clarithromycin (Fig. 7) is a macrolide antibiotic used inHIV infected TB patients to treat the Mycobacterium aviumcomplex (MAC). It has a similar antimicrobial spectrum aserythromycin, but is more effective against certain Gram-
negative bacteria, especially Legionella pneumophila(Nagarajan et al. 2008).
Thioacetazone (Fig. 6) is useful in preventing resis-tance to more powerful drugs like isoniazid andrifampicin. It is never used on its own to treattuberculosis. The use of thioacetazone is declining sinceit can cause severe skin reactions in HIV positivepatients. Thioridazine is also known to kill multidrug-resistant M. tuberculosis. It is no longer recommended fortreatment due its side effects like dry mouth, urination-difficulties, obstipationglaucoma and postural hypotension(Amaral et al. 2004).
Now, the situation is further complicated by the emergenceof multidrug-resistant TB and by infections with lethalsynergy with HIV/AIDS. Patients with MDR-TB are beingtreated with a combination containing second line drugs thatare less effective, more expensive and higher toxicity. TB’slethal synergy with HIV/AIDS puts HIV positive individualswith latent tubercle bacilli infection (LTBI) at a greater risk ofdeveloping active TB, making TB as the number one killeramong patients with AIDS (Kamal et al. 2008).
Properties and mechanism of currently used commonantitubercular agents (Fig. 7)
Primary agents
Isoniazid (nydrazid, laniazid) It is bacteriostatic againstresting cells and bactericidal against dividing organisms.INH is a near ideal antibiotic and very selective.Mycobacteria–MIC ~0.025–0.05 μg/mL and other bacte-ria MIC >500 μg/mL. INH is inexpensive, good oralavailability and low toxicity.
Isoniazid mechanism of action Inhibits mycolic acid bio-synthesis and targets the enoyl-acyl carrier protein reduc-tase enzyme (InhA) involved in mycolic acid synthesis.INH inactivation of IhhA requires metabolic activation
Resistance INH develops quickly resistance in monother-apy and seldom see cross-resistance with other antiTBagents. It is also formulated in combinations, isoniazid andrifampin (Rifamate) and isoniazid, rifampin, and pyrazina-mide (Rifater).
Rifamycins Members of the ansamycin family of naturalproducts from Amicolaptosis mediterranei. It is activetowards a number of bacteria but used almost exclusivelyto tuberculosis
Rifampin (rifadin) Semisynthetic derivative of rifamycin andmost potent antiTB agent with MIC as low as 0.005 μg/mL.
18 M. Asif
Oral or parenteral formulation, it can access CNS but it ismoisture sensitive.
Rifapentine (priftin) It is Cyclopentyl derivative of rifamycin.Advantage over rifampin is less frequent dosing.
Mechanism of action Inhibits bacterial DNA-dependent RNApolymerase and binds to theβ subunit. Blocks elongation of theRNA transcript and prevents gene expression. It is strongCYP450 inducer. One unusual side effect is discoloration ofbody fluids.
Rifamycins are not recommended for use in HIVinfected individuals.
1) trying to reduce incidence of rifamycin resistance and2) rifamycins increase protease inhibitor metabolism.
Two rifamycins available for indications other thantuberculosis
Rifabutin (Mycobutin) used mainly in MAC.Rifaximin (Xifaxan)Indicated for treatment of traveler’s diarrheaEthambutol (Myambutol)
N
NHO NH2
N
N
NH2
O
NH
NH
CH3
CH3
OHHO
Isoniazid Pyrazinamide Ethambutol
ON
N
NR
OH
OH
CH3
O
OCH3
OH
O
CH3
CH3
OH
CH3
OH
CH3
CH3CH3
H3CO
AcO
O
OH
OH
OH
NH
NH
O
OOH
O
NHCH 3OH
OH
HOH 2C
H
NH2
NH
NH2
O R
R = CH3 Rifampicin R = CHO Streptomycin
R= CH2CH(CH3)2 Rifabutin R = CH2OH dihydrostreptomycin
R = Rifapentine
Rifamycin SV Rifaximin
Fig. 2 Structures of first lineanti-tubercular agents
Study of antitubercular agents 19
Orally active and clinically-used (+) isomer is 16x morepotent than meso isomer and 200× more potent than (−)isomer
Mechanism of action Mycolic acids are covalently boundto peptidoglycan via arabinogalactan. EMB inhibits thepolymerization of cell wall arabinan, and results in theaccumulation of the lipid carrier decaprenol phosphoarabi-nose. EMB may interfere with the transfer of arabinose tothe cell wall acceptor.
EMB is usually bacteriostatic and active only towardsactively dividing cells. It is synergistic with rifamycinsbecause EMB enhances intracellular access.
Resistance Results from an acquisition of gene(s) deter-mining overexpression of the Emb proteins can also arisefrom structural mutations in EmbB
Pyrazinamide (aldinamide) Pyrazine analog of nicotin-amide and mechanism suspected to be similar toisoniazid based mostly on structural similarity, notdirect evidence. It also has to be metabolically activat-ed. PZA-resistant strains of M. tuberculosis have amutation in the hydrolase gene.
Streptomycin Is still considered a first line agent but is usedless frequently than the others. It is bactericidal, inactiveagainst intracellular bacilli and no effect against M. avium.Resistance is mostly commonly due to phosphorylation
Secondary/retreatment agents
Aminosalicylic acid (P.A.S. parasal) Orally available asvarious salts, fell out of use because of side effects andfrequent resistance.
Mechanism of action Similar to the sulfonamide antibacte-rials, competitive inhibitor of mycobacterial dihydropter-oate synthase. It is very specific–sulfonamides inactiveagainst M. tuberculosis and PAS is inactive vs. otherbacteria. It is bacteriostatic.
Ethionamide (trecator SC) Developed as an analog ofisoniazide but less potent than INH but very lipophilicand similar mechanism of action as INH.
Requires oxidative activation appears it is by an enzymeother than KatG proposed to form a covalent attachment withInhA
O
O
NH
OH
OHOH
NH2
OH
NH2
CH3
OH
OH
NH2NH2
O OH
NH
NH
NH
NH
NH
NH
NH
NH2
NH
N
NH2
NH2
O
O
NH2
O
OO
O
ONH2
OH
H
Amikacin
NH
NH
NH
NH
NH2
O
NH
NH2O
NH
NH
O
OH
OH O
O
O
NH2
NH2
H
OOH
H
O
HO
NH2H
HOO
O
O
OH
H2N
HO
OH
HO
NH2
HO
NH
O
O
NH2
Viomycin Cylcoserin Kanamycin
2N
Capreomycin
Fig. 3 Structures of differentantibiotics (second line drugs)
20 M. Asif
Cycloserine (seromycin) It is natural product and limited tobeing a retreatment agent because of CNS toxicity.
Mechanism of action Inhibits peptidoglycan formation,specifically-blocks the conversion of L-Ala to D-Ala
No cross-resistance with other antiTB drugs
Capreomycin (capastat) Member of the tuberactinomycinfamily of highly basic cyclic pentapeptides–usually with asixth amino acid as a side chain. Given parenterally andmost potent tuberactinomycins
Mechanism of action It Block protein synthesis andinterferes with initiation, tRNA selection (fidelity) and thechain elongation. It bind to a site on 16S rRNA that isrecognized by aminoglycosides and to the 23S rRNA.Some strains resistant to capreomycin are also resistant tokanamycin
N
O
COOHF
N
NCH3
N
O
COOHF
OCH 3
N
NH
H
H
N
O
COOHF
OCH3
N
HN
CH3
Ciprofloxacin Moxifloxacin R/S: Gatifloxacin
N
O
COOHF
N
N OCH3CH3
N
O
COOHF
N
NH
NH2
F
CH3
CH3
N
O
COOHF
N
N CH 2H5
CH3
CH3
R/S: Ofloxacin Sparfloxacin Enofloxacin
S: Levofloxacin
N
O
COOHF
F
F
NH2
H
H
Trovafloxacin
Fig. 4 Structures of different fluoroquinolones (second line drugs)
Study of antitubercular agents 21
Resistance Acetylation and/or phosphorylation and targetmodification–rRNA methyltransferase.
Kanamycin Most common second-line aminoglycoside andonly given IM.
New/experimental agents
Nitroimidazopyrans First antiTB agents having a novelmechanism of action since the rifamycins. Bicyclic nitro-pyran is key to the pharmacophore.
The C-3 substituent can vary greatly but best activity isseen with lipophilic groups. Stereochemistry at C-3 isimportant S-enantiomers are generally 10× more active thanR-enantiomers
Mechanism of action Affects both lipid and proteinbiosynthesis. Appears to block a late stage in thesynthesis of cell wall mycolic acids. PA-824 must beactivated by M. tuberculosis. Bactericidal against both
replicating and static M. tuberculosis and highly specificfor the MTB complex. PA-824 is being developed bythe Global Alliance for TB
Recently discovered antitubercular agents
The five first-line drugs for treatment are highly effective andthe rate of severe adverse reactions are low and six classes ofsecond line drugs, it may be less effective than the first-linedrugs or it may have more toxic side-effects. However,unpleasant side effects, relatively long duration of treatmentand non-compliance to treatment regimen are drawbacks.Such non-adherence with the course of treatment leads totreatment failure and the development of drug resistance. Thesecond line drugs used for MDRTB are more expensive, lesseffective and more toxic than the five drug standard regimen(Shafii et al. 2008; Nagarajan et al. 2008; Global Tubercu-losis Control 2008).
The goal now is to develop bactericidal drugs in a cost-effective manner, which efficaciously treats infectious
Fig. 6 Currently used antituber-cular drugs and sites of action
Ethionamide Thioridazine p-Aminosalicylic acid Prothionamide
N
NH2S
CH3
N
S
N
S
COOH
OH
NH2 N
NH2S
CH3
Fig. 5 Structures of differentsecond line drugs
22 M. Asif
MDR/XDR strains of M. tuberculosis and latent infectionswith shortened treatment periods as well as reducedfrequency of dosage. Some of recently discovered anti-Tbagents are discussed below.
Tryptanthrin
Tryptanthrin (Fig. 8) is a potent structurally novel indolo-quinazolinone alkaloid, active against MDR strains of M.tuberculosis and the MIC value of it is 0.5–1.0 μg/mL(Mitscher and Baker 1998).
Nitroimidazopyrans and nitroimidaoxazoles
A series of bicyclic nitroimidazopyrans (NAP) haverecently been reported to possess anti-tubercular activity(Fig. 9). One of the compounds, PA-824 has emerged as alead molecule as it is effective against both replicating andlatent M.tuberculosis cells with a MIC ranging from 0.015to 0.25 μg/mL. Poly and multi-drug resistant strains aresusceptible to PA-824, indicating that there is no cross-resistance with current drugs (Tucker et al. 1998). Anotherorally active analog PA 1343 has been developed and is inpreclinical studies with MIC of 0.015 μg/mL. The compoundOPC-67683, a nitro-dihydroimidazooxazole derivative is foundto possess highly potent activity against TB, including MDR-TB at a concentration (MIC) range of 0.006–0.024 μg/mL(Kamal et al. 2008).
First antiTB agents having a novel mechanism of actionsince the rifamycins.
& Structure Activity Relationship of PA-824& Bicyclic nitropyran is key to the pharmacophore& The C-3 substituent can vary greatly but best activity is
seen with lipophilic groups& Stereochemistry at C-3 is important S-enantiomers are
generally 10x more active than R-enantiomers
Mechanism of action
& Affects both lipid and protein biosynthesis& Appears to block a late stage in the synthesis of cell
wall mycolic acids& PA-824 must be activated by M. tuberculosis& Bactericidal versus both replicating and static M.
tuberculosis& Highly specific for the MTB complex& PA-824 is being developed by the Global Alliance for
TB Drug Development& The Global Alliance is a nonprofit group formed in
2000 with the specific goal of bringing new,& affordable TB agents to market by 2010 that would:
& reduce treatment from 9 to 2 months& be affective against latent infections& and/or be effective against MDR-TB
Oxazolidinones
Oxazolidinones (Fig. 10) are totally synthetic, orally activeanti-bacterial agents (Eustice et al. 1998). Some of themorpholine and thiomorpholine analogues of oxazolidi-nones like linezolid and U-100480 have shown potent invitro activity against M. tuberculosis whereas the otheroxazolidinone derivatives display lethal toxicity in the ratmodels (Field and Cowie 2003).
O
CH3
OH
CH3
OH
CH3
CH3
O
CH3
CH3
O
O
CH3
O
O
O
O
OH N
CH3
CH3
CH3
HOOH
CH3
O
CH3
NNH 2
CH3
S
S
Clarithromycin Thioacetazone
NH
Fig. 7 Structures of drugs forHIV/TB
N
N
O
OFig. 8 Structures of tryptanthrin
Study of antitubercular agents 23
Clofazimine analogues
The tetramethyl piperidine substituted phenazines B4169and B4128 (TMP phenazines) have been found to possesssignificantly more activity against M. tuberculosis, includ-ing MDR clinical strains than clofazimines (Fig. 11)(Tangalapally et al. 2005).
Recently, new conjugates of phenazine with phthalimidoand naphthalimido moieties (Fig. 12) have been designedand synthesized as antitubercular compounds. Some of thecompounds in this new class of phenazine have shownpromising results in the inhibition of M. tuberculosis ATCC27294 as well as their clinical isolates. This study revealedthat there is a potential to design such type of phenazinehybrids for the development of new antitubercular agents(Kamal et al. 2008).
Nitrofuranyl amides
A series of nitrofuran derivatives (Fig. 13) which were testedfor MIC activity against M. tuberculosis H37Rv (Gundersenet al. 2002). One compound in this series has shownexcellent MIC90 value 0.025 μg/mL, which is comparableto that of the frontline anti-tubercular agents like isoniazidand ethambutol. Structure-activity relationship studies have
shown that the nitro group is necessary for biologicalactivity.
Purine analouges
9-Benzylpurines (Fig. 14), with a variety of substituents on2, 6 and/or 8 position, have been shown to possess highinhibitory activities against M. tuberculosis. Antimycobac-terial activities of 6-arylpurines and 9-sulphonylated orsulphenylated-6-mercaptopurines are also known in theliterature (Scozzafava et al. 2001; Shindikar and Viswana-than 2005).
Diarylquinolines
A new class of anti-TB agents recently discovered atJohnson & Johnson. More potent than existing agents andstays in body longer–one dose inhibits bacteria growth for aweek. Diarylquinolines are structurally different from bothfluoroquinolones and other quinoline classes. The DARQR207910 (Fig. 15) is a member of a new chemical class ofantimycobacterial agents and has a MIC value equal to orlower than reference compounds. It has a unique specificitytowards mycobacteria including atypical species importantin humans such as MAC, M. kansai, and the fast growers
O
N
N
NO CH3
O
N
O
OCF3O
OPC-67683
N
N OO
O
OOCF3
O N
N OO
O
OCF3
O
O
PA-824 PA-1343
Fig. 9 Structures ofnitroimidazopyrans andnitroimidaoxazoles
O N NO
O
FNH CH3
O S N NO
O
FNH CH3
O
Linezolid U-100480
Fig. 10 Structures of oxazolidinones
24 M. Asif
M. fortium and M. abscessus (Dolezal et al. 2003). Thisantimycobacterial specific spectrum differs from that ofisoniazid, which has very poor activity against MAC.
Works by a novel mechanism of action resistancedevelops in monotherapy. It is being added to thecombination of isoniazid, rifampin and pyrazinamide. Nocross-resistance with other anti-TB agents. To find thecellular target, the genomes of susceptible and resistancestrains were sequenced. Only difference was found in theatpE gene-codes for the proton pump associated with ATPsynthase. Spectrum is primarily limited to Mycobacteria
& More potent than existing agents& Stays in body longer– one dose inhibits bacteria growth
for a week& Works by a novel mechanism of action resistance
develops in Monotherapy& Being added to the combination of isoniazid, rifampin
and pyrazinamide& No cross-resistance with other anti-TB agents& To find the cellular target, the genomes of susceptible
and resistance strains were sequenced.& Only difference was found in the atpE gene– Codes for
the proton pump associated with ATP synthaseSpectrum is primarily limited to Mycobacteria
1,2,4-benzothiadiazines
Sulfonamides are well known for their antibacterial property.1,2,4-benzothiadiazine dioxides have a close relation tosulfonamide (Kamal et al. 2007). Studies in this directionhave afforded some molecules based on 1,2,4-benzothiadia-zine system that exhibited interesting antitubercular activity(Kamal et al. 2006; Jaso et al. 2005). New antitubercularagents 1, 2, 4-benzothiadiazine system was explored byincorporating other heterocyclic rings like pyridine andpyrazine moieties (Fig. 16). Studies in this direction haveafforded some molecules based on 1, 2, 4-benzothiadiazinesystem that exhibited interesting antitubercular activity.Several other molecules like pyrroles, quinoxaline-1,4-diox-ides and alkylsulfinyl amides (Fig. 17), etc. have also beenprepared and tested for their antimycobacterial activity(Zanetti et al. 2005; Slayden et al. 1996).
Thiolactomycin
Naturally occurring (5R)-thiolactomycin (Fig. 18) exhibitspotent in vivo activity against many pathogenic bacteria,including Gram-negative and Gram-positive bacteria andM. tuberculosis. Thiolactomycin is a thiolactone antibioticobtained from fermentation broth of Nocardia species, a
N
N
Cl
NH Cl
N( )2
N N( )n R
R = N
O
O ,
N
O
O
n = 0,1, 2, 3
Fig. 12 Structures of phenazinewith phthalimido andnaphthalimido moieties
N
N
N
NHNH
Cl
ClCl
CH 3
CH 3
CH3 CH 3
ClCl
Cl
N
N
N
NHNH
Cl
Cl
CH 3
CH 3
CH3 CH 3
Cl
Cl
N
N
N
NHCH3
CH3
Cl
Cl
B4169 B4128 Clofazimines
Fig. 11 Structures of clofazimine analogues
Study of antitubercular agents 25
strain of actinomycetes. It shows complete inhibition ofgrowth of the virulent strain M. tuberculosis Erdmman at25 μg/mL (Kamal et al. 2005).
Recently, new conjugates of phenazine with phthalimidoand naphthalimido moieties have been designed andsynthesized as antitubercular compounds Some of thecompounds in this new class of phenazine hybrids haveshown promising results in the inhibition of M. tuberculosisATCC 27294 as well as their clinical isolates (sensitive andresistant). This study revealed that there is a potential todesign such type of phenazine hybrids for the developmentof new antitubercular agents (Malinka 2001). It wasreported that 2 and/or 4-substituted thioquinazoline deriv-atives were identified as a possible pharmacophore forantitubercular activity (Omar and Ahmed 2008).
Pyrrole LL- 3858
Very limited information on the development of pyrroles asanti-mycobacterial agents is currently available. Pyrrolesderivatives were found to be active against standard anddrug-sensitive M. tuberculosis strains in vitro (Deidda et al.1998; Ragno et al. 2000) Lupin Limited reported theidentification of a Pyrrole derivative (LL-3858) that showedhigher bactericidal activity than Isoniazid when adminis-tered as monotherapy to infected mice.
In mouse models, a 12 weeks treatment with LL- 3858plus isoniazid and rifampicin, or LL-3858 plus isoniazid-rifampicin-pyrazinamide, sterilized the lungs of all infectedmice. Experiments conducted in mice and dogs showed thatthe compound is well absorbed, with levels in serum abovethe MIC and better half-life and Cmax than those showedby isoniazid. No information is available concerning themolecular mechanisms that mediate LL-3858’s bactericidal
activity. Pyrrole LL3858 is currently in Phase I ClinicalTrials (Lupin Limited, Paris 2005)
Pleuromutilins
The pleuromutilins represent a novel class of antibioticsderived from a natural product. They interfere with proteinsynthesis by binding to the 23S rRNA and thereforeinhibiting the peptide bond formation (Schlunzen et al.2004). Despite the novelty of this class of compounds,recent studies have shown that cross-resistance might occuramong pleromutilins and oxazolidinones (Long et al. 2006).Pleuromutilins have been shown to inhibit the growth of M.tuberculosis in vitro. The goal of this project is theidentification of a pleuromutilin derivative that is activeagainst MDR-TB and allows shortening of the treatment(Global TB Alliance Annual report 2004–2005).
Dipiperidine
Dipiperidine SQ-609 is a novel compound structurallyunrelated to existing anti-TB drugs. It kills M. tuberculosisby interfering with cell wall biosynthesis (precise mecha-nism unknown). Antimicrobial activity has been demon-strated in vivo in mouse models (Nikonenko et al. 2004);(Kelly et al. 1996)
ATP synthase inhibitor FAS20013 (FASgene)
FAS20013 is a novel compound identified by Fasgen. Itbelongs to the class of ß-sulphonylcarboxamides. Fasgenclaims that “FAS20013 will kill more organisms in a 4-hourexposure than isoniazid or rifampicin can during a 12- to14-day exposure. The compound is very effective in killingMDR-TB organisms that are resistant to multiple drugscurrently in use. A series of recent laboratory experimentsindicates the superior effect of FAS20013 compared tocurrent drugs in terms of its ability to “sterilize” TB lesionsand kill latent TB. Therapeutic evaluation of FAS20013 hasrepeatedly shown its effectiveness in mice, and appears tohave no serious side effects. The compound is up to 100%bioavailable when administered orally. To date no dose-limiting toxicity has been encountered, even when doses 10times the effective dose were administered.” The compoundis thought to act through inhibition of ATP synthase.However, available scientific publications assessing theefficacy of this compound are of poor quality. (Jones et al.2000; Parrish et al., 2004)
Translocase I inhibitor (Sequella Inc.)
Sequella is developing a series of translocase inhibitors forthe potential treatment of tuberculosis.
N
NN
N
O
CH3
Fig. 14 Structure of 2-chloro-4-(2-furanyl)-9-benzopurine
O
NH
N
N
CH3
O
O2N
F
Fig. 13 Structure of nitrofuran derivatives
26 M. Asif
The compounds specifically inhibit mycobacterial translo-case I, an enzyme required for bacterial cell wall synthesis.Preclinical evaluation of the compounds is planned. (http://www.sequella.com/pipeline/translocaseinhibitor.asp.).
InhA inhibitors (GlaxoSmithKline-TB alliance)
InhA, the enoyl reductase enzyme from Mycobacteriumtuberculosis, catalyses the last step in the fatty acidbiosynthesis pathway (FAS II). Frontline anti-tuberculosisdrugs such as isoniazid (INH) target this enzyme. Drugresistance to INH results primarily from mutations in KatG,the enzyme that activates INH. Consequently, InhAinhibitors that do not require activation by KatG areattractive candidates for drug discovery. The main purposefor this screen is therefore to bypass the activation step anddirectly inhibit InhA. A possible limitation for this kind ofcompounds is that cross-resistance with isoniazid mayeasily occur. Indeed, mutations in InhA encoding genehave been already identified in INH-resistance strains(Banerjee et al. 1994) even if they occur less frequentlythan KatG mutations.
Isocitrate lyase inhibitors
The isocitrate lyase (ICL) enzyme has been shown to beessential for long-term persistence of M.tuberculosis in
mice, but not required for bacilli viability in normal cultureor hypoxic conditions (McKinney et al. 2000). McKinneyand collaborators have recently shown that inhibition ofICL1 and ICL2, the two isoforms of isocytrate lyase presentin M.tuberculosis, blocks growth and survival of M.tuberculosis bacteria in macrophages and in mice at earlyand late stage of infection. The absence of ICL orthologs inmammals should facilitate the development of glyoxylatecycle inhibitors as new drugs for the treatment fortuberculosis. Such a new drug is expected to be able tokill persistent bacteria and therefore have sterilizing activityand shorten treatment time. Guided by the three-dimensional structure of isocitrate lyase (Sharma et al.2000). The structure of ICL active site is making thescreening for inhibitors particularly lengthy and laborious.The active site of this enzyme, indeed, appears not to beeasily and effectively reached by compounds (J McKinneypersonal communication).
Compounds originating from existing families of drugs
Using existing fluoroquinolones for TB?
Fluoroquinolones were introduced into clinical practice inthe 1980s. Characterized by broadspectrum antimicrobialactivity, they are recommended and widely used for thetreatment of bacterial infection of the respiratory, gastroin-testinal and urinary tracts (Bartlett et al. 2000; Neu 1987).Fluoroquinolones have been also found to have activityagainst M. tuberculosis (Grosset 1992; Tsukamura et al.1985) and are currently part of the recommended regimenas second-line drugs. Since fluoroquinolones share thesame molecular targets, it is highly probable that they willtrigger the same mechanisms of resistance. Indeed, cross-resistance has been reported within the fluoroquinoloneclass such that reduced susceptibility to one fluoroquino-lones likely confers reduced susceptibility to all fluoroqui-
NS
NNH
NH
X Z
Y
OO
O
R1
R
NS
N
OOR
1
R
NH
Z
X
Y
O
R = Me, Et, i-Pr, Ph R = Me, Ph
R1 = H, Cl, R1 = H, Cl,
X = CH, N X= CH, N ,
Y = CH, N Y = CH, N,
Z = CH, N, CCl Z = CH, N, CCl
Fig. 16 Structure of 1,2,4-ben-zothiadiazine by incorporatingpyridine and pyrazine
N O
CH3
BrO
HN
CH3
CH3(R)
(S)
Fig. 15 Structure of diarylquinoline (R207910)
Study of antitubercular agents 27
nolones (Alangaden et al. 1995; Ruiz-Serrano et al. 2000);for review see (Ginsburg et al. 2003a). The major concernis that widespread use of fluoroquinolones for treatment ofother bacterial infections may select for resistant strains ofMycobacterium tuberculosis. Fluoroquinolones susceptibil-ity is not routinely assessed in clinical isolates of tuberclebacilli, so there is not much information available about theprevalence of fluoroquinolone resistance in M. tuberculosis.The concluded that despite the widespread use of fluo-roquinolones for treatment of common bacterial infection,resistance to fluoroquinolones remains rare and occursmainly in multi-drug resistant strains (Bozeman et al.,2005). Cross-resistance was observed among the differentfluoroquinolones tested (ofloxacin, levofloxacin, gatifloxacin,moxifloxacin, and ciprofloxacin) (Ginsburg et al. 2003b).
In conclusion, there are reasons for concerns about therapid development of resistance particularly when fluoro-quinolones are administered as the only active agent in afailing multi-drug regimen. A controlled study of rifabutinand an uncontrolled study of ofloxacin in the retreatment ofpatients with pulmonary tuberculosis resistant to isoniazid,streptomycin and rifampicin (Alangaden and Lerner 1997;Yew et al. 1990). Moreover, the risk of selectingfluoroquinolone-resistant M. tuberculosis strains by empir-ically treating with fluoroquinolones other presumed infec-tions before a diagnosis of tuberculosis is established is ofgreat concern. For this reason some investigators in the TBfield argue that the use of fluoroquinolones might be betterreserved for specific serious infection such as tuberculosisrather than becoming the workhorse of antimicrobialtreatment; however, given the current widespread use ofquinolones this might not be realistic.
Lately, the interest on fluoroquinolones as antitubercu-losis agent has focused on the new fluoroquinolonesmoxifloxacin (MXF) and gatifloxacin (GTF). Despite alack of a comprehensive work comparing the activities ofold and new classes of Fluoroquinolones in M. tuberculo-sis, what can be inferred from published results is thatmoxifloxacin and gatifloxacin are characterized by a higheractivity against M. tuberculosis in vitro when compared tothe old fluoroquinolones ofloxacin and ciprofloxacin (Hu etal. 2003; Paramasivan et al. 2005; Rodriguez et al. 2001;Sulochana et al. 2005). These new compounds are currentlytaken in consideration as anti-tuberculosis first-line drugs.A more detailed analysis of the properties of the newfluoroquinolones moxifloxacin and gatifloxacin will followin the next paragraphs.
Gatifloxacin
Marketed in the U.S. by Bristol-Myers Squibb as Tequin,Gatifloxacin (GAT) has been found to have in vitro and invivo bactericidal activity against M. tuberculosis ((Hu et al.2003);(Alvirez-Freites et al. 2002)). In an in vitro studyusing stationary-phase mycobacterial culture, gatifloxacin(4°g/ml) showed the highest bactericidal activity during thefirst 2 days but not thereafter (Paramasivan et al. 2005).Similar results were obtained when gatifloxacin was used incombination with isoniazid or rifampicin: gatifloxacin wasable to slightly increase the bactericidal activity of INH orRIF only during the first 2 days (Paramasivan et al. 2005).This is in contrast with other studies showing thatgatifloxacin and moxifloxacin had similar bactericidalactivity on a stationary-phase culture of M. tuberculosisand comparable to the bactericidal activity of rifampicin(Hu et al. 2003; Lenaerts et al. 2005). One paper reportedthat when tested in mice in combination with Ethionamideand Pyrazinamide (high doses: 450 mg/kg, 5 days perweek) gatifloxacin was able to clear the lungs of infectedanimals after 2 months of treatment (Cynamon and Sklaney2003). Thus, currently available data on gatifloxacin do notsupport the hypothesis that introduction of gatifloxacin infirst-line regimen will impressively contribute to shortenTB treatment. Further investigation should be addressed toproperly assess the activity of gatifloxacin in vitro and inmouse models. Nevertheless, gatifloxacin is currently in
SO
OH
CH2
CH3
CH3
CH3
(5R)-Thiolactomycin
Fig. 18 Structure of thiolactomycin
N
Cl
Cl
CH3
N N
N+
N+
CH3
O
Cl
O-
O-
NH2S
H21C10
OO
O
Fig. 17 Structure of some newcompounds with pyrrole,quinoxaline-1,4-dioxide and al-kyl sulfinyl amide moieties
28 M. Asif
Phase III Clinical Trials, conducted under the supervisionof the European Commission Oflotub Consortium,WHOTDR, NIAID TBRU, Tuberculosis Research Centre.The aim of the trial is to evaluate the efficacy and safety ofa 4 months gatifloxacin-containing regimen for the treat-ment of pulmonary tuberculosis.
Moxifloxacin
Moxifloxacin is the most promising of the new fluoroqui-nolones being tested against M. tuberculosis. In vitro,moxifloxacin appeared to kill a subpopulation of tuberclebacilli not killed by rifampicin, i.e. rifampicin-tolerantpersisters, while the older fluoroquinolones ciprofloxacinand ofloxacin did not have any significant bactericidaleffect on the same subpopulation (Hu et al. 2003). Onepossibility is that moxifloxacin interferes with proteinsynthesis in slowly metabolising bacteria through a mech-anism that differs from that used by rifampicin. However,the molecular mechanisms beyond such a bactericidalactivity still await further characterization.
In mouse models the activity of moxifloxacin againsttubercle bacilli was comparable to that of isoniazid(Miyazaki et al. 1999). Moreover, when used in combina-tion with moxifloxacin and pyrazinamide, moxifloxacin hasbeen reported to kill the bacilli more effectively than theisoniazid + rifampicin + pyrazinamide combination. Indeed,cultures from lungs of mice treated with rifampicin-moxifloxacinpyrazinamide for 2 months followed by rifampi-cinmoxifloxacin resulted negative upon 4 months of treatment,while mice that received rifampicinisoniazid- pyrazinamide/rifampicin-isoniazid showed complete culture conversion after6 months of treatment (Nuermberger et al. 2004a). Further-more, no relapse was observed in mice treated for at least4 months with the combination rifampicinmoxifloxacin-pyrazinamide, while mice treated with rifampicin-isoniazidpyrazinamide required 6 months of treatment beforeno relapse could be detected (Nuermberger et al. 2004a, b).The authors explain the better activity of the rifampicin-moxifloxacin-pyrazinamide combination over the rifampicin-INH-pyrazinamide combination as the consequence of apossible synergism in the antituberculosis activity of the threedrugs rifampicin, moxifloxacin and pyrazinamide. Alterna-tively, substitution of moxifloxacin with isoniazid in thestandard regimen could relieve a possible antagonism amongthe currently used drugs (Grosset et al. 1992).
To summarise, results obtained so far in in vitro and in vivostudies suggest that moxifloxacin might be a promisingcandidate drug to shorten TB treatment. At the molecularlevels, the reason for its improved efficiency is mainly aconsequence of its poor susceptibility to active efflux thatensures the maintenance of high intracellular concentration.Shortening of therapy in mouse models seems to be mainly
due to a released of antagonism among the drugs in theregimen. There is a possibility that moxifloxacin might beactive against slowly metabolising bacteria by inhibitingDNA transcription and, consequently, mRNA and proteinsynthesis, therefore having a mild sterilizing activity. How-ever, this still needs to be rigorously proven. As far asemergence of resistance is concerned, in vitro studies in S.pneumoniae revealed that moxifloxacin, used at concentrationabove the minimal inhibitory concentration (MIC), is lessprone to select first-step mutants when compared to thefluoroquinolone sparfloxacin. However, moxifloxacin mono-therapy in mice models showed that resistance to moxiflox-acin might rapidly emerge (Ginsburg et al. 2005).
Moxifloxacin is currently in Phase II Clinical Trials. A trialsubstituting ethambutol with moxifloxacin during intensivephase (TBTC 27) was initiated before above cited animalstudies had been conducted and showed no advantage overethambutol. Preliminary results of this study have beenpublished and showed that moxifloxacin containing regimendid not present increased sterilizing activity (measured as theability to induce sputum colture conversion upon 2 month oftreatment) over the standard regimen. However moxifloxacin-containing regimen did show increased activity at earlier timepoints (Burman et al. 2006).
New quinolones
Synthesize and evaluate novel and more effective quinolonecompounds that could shorten first-line treatment. To date,450 compounds have been synthesized and tested for theiranti-TB activity. During this work, the sub-class termed 2-pyridones has been identified as the one showing mostpotent activity against M. tuberculosis in both its growingand persistant state. This sub-class of compounds found tohave activity against drug-susceptible and drug resistant M.tuberculosis (Oleksijew et al. 1998). In June 2005, the TBAlliance contacted Abbott and was granted rights todevelop for TB indication this class of DNA gyraseinhibitors which is otherwise protected by certain Abbottpatents. As fluoroquinolones, 2-pyridones are inhibitors ofDNA gyrase (Flamm et al. 1995). Current work is focusedon the modification of a position which influences activity,pharmacokinetics and safety profile. The lead compoundsidentified so far showed better activity than gatifloxacin andmoxifloxacin. At present, the project is in the leadoptimisation stage and aims to obtain a final candidate bythe end of 2006 (TB Alliance Annual report 2004/2005)
Non-fluorinated quinolones
Recently, a series of 8-methoxy non-fluorinated quinolones(NFQs) have been developed by Procter &Gamble. NFQs lacka 6-fluorine in their quinolone nucleus differentiating them
Study of antitubercular agents 29
from fluorinated quinolones such as gatifloxacin and moxi-floxacin. NFQs target a broad spectrum of bacteria and theyseem to act preferentially through inhibition of DNA gyrase.NFQs are currently being tested against M. tuberculosis.
Diamine SQ-109
Diamine SQ-109 has been identified in a screening performedby Sequella Inc. using a combinatorial library based on thepharmacophore of ethambutol. The aim was to develop asecond-generation agent from the first line drug ethambutol.When tested in mice using a low-dose infection model of TB,SQ-109 at 1 mg/kg was as effective as ethambutol at 100 mg/kg. However SQ-109 did not show improved effectiveness athigher doses (10 mg/kg; 25 mg/kg) and was clearly lesseffective than isoniazid (Protopopova et al. 2005). Protopopovaand collaborators claim that SQ-109 is effective against drug-resistant strains of M. tuberculosis, including those that areethambutol-resistant, and that it targets different intracellulartarget(s). For this reason it can be considered as a new TBdrug and not simply as an ethambutol analogue.
Macrolides
The aim of this project, launched by the TB Alliance incollaboration with the Institute for TB research of theUniversity of Illinois in Chicago, is to optimize the anti-TBactivity of the macrolide antibiotics through the synthesis ofadditional chemically modified derivatives of erythromycin.More than 200 derivatives have been synthesized and threeseries were identified as having anti-tuberculosis activitysuperior to that of the benchmark clarythromicin. Members ofthese series have exhibited potent anaerobic activity andappears to be safe in use with ARVs (TB Alliance Annualreport 2004/2005).
Thiolactomycin analogs
Thiolactomicin (TLM) was the first example of naturallyoccurring thiolactone to exhibit antibiotic activity. Thecompound has moderate in vitro activity against a broadspectrum of pathogens, including Gram-positive and Gram-negative bacteria and M. tuberculosis. Analogs of thiolac-tomicin have been synthesized and found to have enhancedactivity against whole cells of pathogenic strain of M.tuberculosis (Douglas et al. 2002). TLM analogs seem toact through the inhibition of the mycolate synthase, anenzyme involved in the biosynthesis of the cell wall.
Nitrofuranylamides
M. tuberculosis is quite susceptible to Nitrocontainingcompounds (Sun and Zhang 1999) (Murugasu-Oei and
Dick 2000). Nitrofuranylamide was identified in a screen-ing for UDP-Gal mutase inhibition. An expanded set ofnitrofuranylamides was synthesized and tested for anti-microbial activity. This led to the identification of a numberof nitrofuranylamides with activity against M. tuberculosis.However, the further investigation has revealed that theprimary target for nitrofuranylamides antimicrobial activityis not the UDP-gal mutase. Four compounds of thenitrofuranylamides class showed significant activity inmouse models for TB infection (Tangallapally et al. 2004)
Nitroimidazole analogs
While pursuing PA-824’s remaining development activities,this class of compounds by identifying superior compoundsand improving on PA-824’s properties as a drug. M.tuberculosis Dihydrolipoamide Acyltranferase (dlaT) is acomponent of two important multi-subunit complexes:pyruvate dehydrogenase, the enzyme that catalyses thesynthesis of Acetyl Coenzyme A, and peroxynitrite reductase,a defence against oxidative/nitrosative stress (Tian et al.2005); (Shi and Ehrt 2006). DlaT has been shown to berequired for full virulence in vivo in mice, while in in vitroexperiments mouse macrophages can readily kill intracellularM. tuberculosis mutants lacking dlaT (Shi and Ehrt 2006).The aim is to identify compounds that are active againstspecific distinct molecular targets, including inhibitors ofDNA gyrase (the target of fluoroquinolones), peptidedeformylase (PDF) inhibitors and analogs of quinoloneelectron transport inhibitors.
Bacterial peptide deformylase belongs to a subfamily ofmetalloproteases catalysing the removal of the N-terminalformyl group from newly synthesized proteins. PDF isessential for bacterial growth but is not required by mamma-lian cells, so represents a promising target for the developmentof a new generation of broad-spectrum antibacterial agents.Two PDF inhibitors, VIC-104959 (LBM415) and BB-83698,have progressed to Phase I clinical trials (Jain et al. 2005). ThePDF inhibitor BB-3497 was recently found to have potent invitro activity against M. tuberculosis (Cynamon et al. 2004).This finding suggests that PDF inhibitors can find applica-tion in TB treatment. Beside the project jointly launched byGSK and the TB Alliance, researcher at the NovartisInstitute for tropical Disease (NITD) are also working onidentification of PDF inhibitors for TB treatment (NITDSymposium on Tuberculosis, 2005).
Inhibition of electron transport can lead to ATP depletionand decline in intracellular redox potential. Recently, anti-tubercular drugs targeting ATP synthesis (i.e. diarylquinoline)have been shown to be particularly effective, even againstnon-replicating bacteria. Therefore, identification of com-pounds able to inhibit the electron transport process could leadto the development of more effective drugs active against both
30 M. Asif
replicating and non-replicating bacilli. Others drugs candidatethat could find an application in TB treatment are:
New rifamycin derivatives
Rifalazil, a new semisynthetic rifamycin, is characterizedby a long half-life and is more active than rifampicin andrifabutin against M. tuberculosis both in vitro and in vivo(Hirata et al. 1995; Shoen et al. 2000). However, high levelrifampicin –resistant strains present cross-resistance to allryfamycins (Moghazeh et al. 1996).
Oxazolidinones (linezolid)
Oxazolidinones are a new class of broad-spectrum anti-biotics developed by Pharmacia. They inhibit proteinsynthesis by binding to the 50S subunit of ribosomes.Oxazolidinones had significant activities against M. tuber-culosis in vitro and in mice (Cynamon et al. 1999; Zurenkoet al. 1996). However, oxazolidinones are seen as lesspromising due to their toxicity and high price.
Other agents used/investigated to treat mycobacterialinfections
Some β-lactams in combination with β-lactamase inhib-itors, fluoroquinolones–especially derivatives that are activein the acidic internal environment of the macrophage,clarithromycin is now indicated to treat MAC.
Results
In view of the persistent drug-resistant TB problem ofcurrently used antitubercular agents, it is important that newantitubercular molecules or drugs should address differenttargets, as those of currently used drugs including theshortening of TB therapy. The unique structure of themycobacterial cell wall makes it a useful target for drugdevelopment and studies can be directed to specific sites likecell wall biosynthetic pathways (Heath and Rock 2004; Oishiet al. 1982). For example, thiolactomycin has a uniquechemical structure with no chemical relation to any group ofknown antibiotics inhibits mycobacterial fatty acid synthaseand the elongation steps of mycolic acid biosynthesis(Slayden and Barry 2002; Tripathi et al. 2005) withnegligible toxicity and thus structures based on this lead orsome other new molecules could provide a new class ofchemotherapeutic agents against tuberculosis (Tomioka andNamba 2006).
Although one possible long term solution to the problemis a better vaccine, in the short term, the major reliance willbe on chemotherapy (Berning 2001) requiring the develop-
ment of novel, effective and non-toxic antitubercular agents(Pasquato and Ferreira 2001). The identification of noveltarget sites will also be needed to circumvent theproblems associated with the increasing occurrence ofmulti-drug resistant strains. To do this, biochemicalpathways specific to the mycobacteria and relatedorganisms’ disease cycle must be better understood.Many unique metabolic processes occur during thebiosynthesis of mycobacterial cell wall components.One of these attractive targets for the rational designof new antitubercular agents are the mycolic acids, themajor components of the cell wall of M. tuberculosis(Stover et al. 2000).
From the chemotherapeutic point of view, there are twosources of new chemical entities. The first is the extraor-dinary diversity provided by natural products. The secondresults from the design of new or the modernization ofsynthetic transformations (Tomioka and Namba 2006).
Future prospectives and drug development
Development of new chemotherapeutic drugs is the need tocontrol tuberculosis. In the last 40 years no new compoundhas been brought to the market for the treatment of tuberculardisease. However, in recent years there is an enhanced activityin the research and development of new drugs for TB. Somecompounds are presently in clinical development, whileothers are being investigated pre-clinically in an attempt toexplore new molecules for the target based treatment of TB.Simultaneously some new targets are being identified andvalidated for their practical usefulness. The present reviewprovides an overview of the pyridazinones against pathogenicmycobacterium (Kamal et al. 2008).
The specific goal of bringing new, affordable TB agentsthat would:
& reduce treatment from 9 to 2 months& be affective against latent infections& and/or be effective against MDR-TB& Cheap and easily available.
Discussion
Inspite of the availability of the BCG vaccine and somechemotherapeutic agents, TB remains a leading infectiouskiller worldwide. This is mainly due to the lack of newdrugs in the market, particularly for effective treatmentagainst the spread of MDR and XDR, and patients co-infected with HIV/AIDS. Therefore, there is an urgent needfor the development of new anti-TB drugs with lesser side-effects, improved pharmacokinetic properties including the
Study of antitubercular agents 31
resistant strains. More importantly, the newly developeddrugs are required to reduce the overall duration of treatment.It is also important to note that in the development of newdrugs, action based on inhibition of bacterial targets, thus weneed to understand host factors such as immune mechanisms,genetic susceptibility and disease relapse. Therefore, thenewer anti-TB compounds need to be developed on theunderstanding of the molecular mechanisms of drug actionand drug resistance. One of the well established broadspectrum antibacterial drug targets that have been veryeffective is the inhibition of cell wall biosynthesis. Some ofthe anti-TB agents like isoniazid and ethambutol targetdifferent aspects of the cell wall biosynthesis.
Focusing on the existing antitubercular targets for drugdevelopment may be of limited value because chances ofresistance by mutation in the protein target may render thedrugs ineffective. Precisely, because of this observed drug–resistance by the bacterium, it is imperative to developsmart new drugs that inhibit novel targets that arestructurally and functionally different from those currentlyknown. Medicinal chemists will be interested to working onnew compounds for their wide range of biological activitiesparticularly against mycobacterium with minimum orwithout side effects. The pharmaceutical industry however,has generally shown little interest in developing new, moreeffective drugs to address these needs, and as a result, nonew anti-TB agent with a novel mechanism of action hasbeen launched for last 40 years.
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