Recent Advances in The Development of Anti-Tuberculosis Drugs Acting On Multidrug-Resistant Strains: A Review

International Journal of Research in Pharmacy and Biosciences
Volume 2, Issue 5,June 2015, PP 1-18

ISSN 2394-5885 (Print) & ISSN 2394-5893 (Online)
Recent Advances in the Development of Anti-tuberculosis Drugs

Acting on Multidrug-Resistant Strains: A review
Amanuel Godebo*1, Abiy H/woldi2, Alemayehu Toma3
1
Department of Pharmacology, School of Medicine, College of Health Sciences, Addis Ababa University, Addis
Ababa, Ethiopia
2Department of Pharmacology, School of Medicine, College of Health Sciences, Addis Ababa University, P. O.
Box 9086, Addis Ababa, Ethiopia
3
Pharmacology Department, School of Medicine, Hawassa University, Hawassa, Ethiopia
ABSTRACT
Despite over a century of drug development research, tuberculosis remains a major public health problem with a
leading cause of infectious death worldwide. The reality of being deadly is the result of decades of neglect for
an important infectious disease, lack of resources for national TB control programs, poor case detection and
inadequate/inappropriate therapy in high-burden countries. At present time, the outcome of treatment protocol
for MDR-TB is not intrinsically satisfactory, and it is lengthy in duration (18 – 24 months) although the
treatment regimen consists of at least four drugs with different mechanism of action. Hence, new drugs are
urgently needed to shorten and improve the treatment course in drug resistant TB, and to minimize the
occurrence of new infections and death to zero level. Nowadays, various novel investigational drugs, such as
bedaquine (TMC207) [approved for use by FDA and WHO Expert Group], nitroimidazoles (PA-824, OPC-
67683), diamines (SQ109), oxazolidinones(Linezolid, PNU-100480 (Sutezolid), ADZ5847), pyrroles (LL3858)
and fluoroquinolones (moxifloxacin and gatifloxacin), have entered various clinical trial phases and on progress
to be developed for the treatment of MDR-TB. However, new targets should be further identified and
discovered that can kill the viable MTB in the latent phase and prevent the occurrence of resistance in bacterial
cells. Finally, it is crucial to boost the connection between different parties, like research and development
institutes, industries, drug control authorities, and international policy-making bodies to make the future bright
and convey the optimum therapy for the patients who are suffering from TB.
Keywords: Tuberculosis, MDR-TB, treatment protocol, new targets, challenges.
INTRODUCTION
Background
Tuberculosis (TB) remains a major global health problem. It causes ill-health among millions of
people each year and ranks as the second leading cause of death from an infectious disease
worldwide, after the human immunodeficiency virus (HIV). According to World Health Organization
(WHO) global TB report 2012, there were almost 9 million new cases in 2011 and 1.4 million TB
deaths. Besides, the emergence of drug-resistance is becoming a major threat to global TB care and
control. WHO estimates that around 310,000 multidrug-resistant tuberculosis (MDR-TB) cases
occurred among notified TB patients in 2011.1The increasing emergence of drug resistant TB, and
HIV infection, which compromises host defense and allows latent infection to reactivate TB, pose
further challenges for effective control of the disease. Moreover, TB treatment is remarkably lengthy
(takes 6–9 months) with significant toxicity, which creates poor patient compliance resulting in a
frequent cause for selection of drug resistant and often deadly MDR-TB bacteria.2To tackle this
situation, multiple approaches will need to be implemented simultaneously, combining the efforts of
government, academic and industrial entities. These approaches include increased funding for
research in antibiotic resistance and drug development for TB, development of methods for protecting
the efficacy of existing drugs, and prioritization for making use of current non-TB drugs for TB
treatment.3
*Address for correspondence

alemayehutoma@gmail.com
International Journal of Research in Pharmacy and Biosciences V2 ● I5 ● June 2015 1
Amanuel Godebo et al. “Recent Advances in the Development of Anti-tuberculosis Drugs Acting on
Multidrug-Resistant Strains: A Review”
Current treatment regimens for MDR-TB are far from satisfactory: the overall duration is 20 months
or more, requiring daily administration of drugs that are more toxic and less effective than those used
to treat drug-susceptible TB, and have a high cost. Among MDR-TB patients started on treatment
globally in 2009, only 48% were treated successfully, largely as a result of a high frequency of patient
deaths (15%) and loss to follow-up (28%), which is commonly associated with adverse drug
reactions, among other factors. New drugs that would help build a better, safer, less toxic, shorter and
cheaper regimen are therefore urgently needed to reduce patient suffering and mortality.4It has been
over 40 years since a new drug for tuberculosis has been discovered.5 Therefore, the development of
innovative, effective drug combinations should also be encouraged to diversify therapeutic choices,
especially those for drug resistant TB cases. Emphasis, however, should be placed on compounds that
attack non-traditional targets, as to lower the risk for acquired drug resistance mechanisms.3
Epidemiology
Globally in 2011, there were an estimated 630,000 cases of MDR-TB (range, 460 000–790 000)
among the world’s 12 million prevalent cases of TB, in which 3.7% of new cases and 20% of
previously treated cases were anticipated. Almost 60% of these cases were in India, China and the
Russian Federation. While the number of cases of MDR-TB notified in the 27 high MDR-TB burden
countries is increasing and reached almost 60,000 worldwide in 2011, this is only one in five (19%) of
the notified TB patients estimated to have MDR-TB.1
TREATMENT AND MANAGEMENT OF MDR-TB
The current MDR-TB epidemic is the result of decades of neglect for an important infectious disease,
lack of resources for national TB control programs, poor case detection and inadequate/inappropriate
therapy in high-burden countries. Initial outbreaks of MDR-TB in developed countries were
associated with very high mortality rates both in HIV-negative and HIV-coinfected patients.
Optimization of treatment regimens together with rapid diagnosis and drug susceptibility testing
(DST) for first- and second-line drugs, greatly improved the clinical outcome. However, in
developing countries, the prognosis is still largely poor due to inadequate laboratory support that is
critical for successful management of MDR-TB patients.6
Treatment of drug-resistant TB requires a combination various anti-TB drugs with different
mechanisms of action. Traditionally, the classes of anti-TB drugs have been divided into first- and
second-line drugs as briefly explained in Table 1. Besides, there are some other agents with unclear
efficacy (not recommended for routine use) being used for the treatment of MDR-TB and XDR-
TB.7For MDR treatment, anti-TB drugs are grouped according to efficacy, experience of use and drug
class, as shown in Table 2. All the first-line anti-TB drugs are in Group 1, except streptomycin (SM),
which is classified with the other injectable agents in Group 2. All the drugs in Groups 2–5 (except
SM) are second-line, or reserve drugs. Treatment regimens should consist of at least four drugs with
either certain, or almost certain, effectiveness. Each dose in an MDR regimen is given as directly
observed therapy (DOT) throughout the treatment.8
Table1. Some of Anti-TB drugs with their category and mechanism of action
Drug Name Category Route Chemical Description Mechanism of Action
Isoniazid (INH) 1st line Oral Nicotinic acid Inhibits mycolic acid synthesis
hydrazide
Rifampin/rifampicin 1st line Oral Rifamycin derivative Inhibits RNA synthesis by
(RIF) targeting RNA polymerase
Pyrazinamide (PZA) 1st line Oral Nicotinamide Inhibits cell membrane synthesis
derivative
Ethambutol (EMB) 1st line Oral Ethylene di-imine di- Inhibit cell wall synthesis
1-butanol
Streptomycin (SM) 1st line Injectable Aminoglycoside Inhibits protein synthesis
Rifabutin (Rfb) 2nd line Oral Rifamycin derivative Inhibits RNA synthesis by
/Rifapentine targeting RNA polymerase
Amikacin (Am) 2nd line Injectable Aminoglycoside Inhibits protein synthesis
Kanamycin (Km) 2nd line Injectable Aminoglycoside Inhibits protein synthesis
Capreomycin (Cm) 2nd line Injectable Cyclic peptide Inhibits protein synthesis
Ofloxacin (Ofx) 2nd line Oral Fluoroquinolone Inhibits DNA synthesis and
2 International Journal of Research in Pharmacy and Biosciences V2 ● I5 ● June 2015

supercoiling by targeting
toposiomerase
Levofloxacin (Lfx) 2nd line Oral Fluoroquinolones Inhibits DNA synthesis and
toposiomerase
Moxifloxacin (MFX) 2nd line Oral Fluoroquinolones Inhibits DNA synthesis and
toposiomerase
Ethionamide (Eto) 2nd line Oral Isonicotinic acid Inhibits mycolic acid synthesis
derivative
Protionamide (Pto) 2nd line Oral Isonicotinic acid Inhibits mycolic acid synthesis
derivative
Cycloserine (Cs) 2nd line Oral D-Cycloserine Inhibits cell wall synthesis
Paraaminosalicylicacid 2nd line Oral Para-amino salicylic Inhibit folate biosynthesis
(PAS) acid
Table2.Groups of Drugs to Treat MDR-TB
Group Class Drugs
Pyrazinamide (PZA)
Group 1 First-line oral agents Ethambutol (EMB)
Rifabutin (RFB)
Kanamycin (Km)
Amikacin (Am)
Group 2 Injectable Agents Capreomycin (Cm)
Streptomycin (SM)
Levofloxacin (lfx)
Group 3 Fluoroquinolones Moxifloxacin (mfx)
Ofloxacin (ofx)
Para-aminosalicylic acid (PAS)
Cycloserine (Cs)
Group 4 Oral bacteriostatic second-line Terizidone (Trd)
agents Ethionamide (Eto)
Protionamide (Pto)
Clofazimine (Cfz)
Linezolid (Lzd)
Amoxicillin/Clavulanate (Amx/clv)
Group 5 Agents with unclear role in Thioacetazone (Thz)
treatment of drug resistant-TB Imipenem/Cilastatin (Ipm/Cln)
High-dose isoniazid (high-dose H)
Clarithromycin (Clr)
Programmatic approaches to MDR-TB treatment depend in part on the type of laboratory method
(Conventional and Rapid DST) used to confirm MDR-TB, as shown in Table 3. Once MDR-TB is
confirmed, patients can be treated with: a standard MDR-TB regimen (standardized approach); or an
individually tailored regimen, based on DST of additional drugs, as shown in Table 4.8
Table1. MDR-TB Treatment Strategies Depending on Laboratory Method to Confirm MDR-TB
Laboratory Method DST Result Treatment Approach
While awaiting DST results for
isoniazid, rifampicin; MDR-TB Empirical treatment with MDR-TB regimen
is suspected
Conventional method to
Continue standard MDR-TB regimen or
detect MDR-TB
Once MDR-TB is confirmed Change to individualized MDR-TB regimen
(once susceptibility testing for second-line
drugs is available).
Standard MDR-TB regimen or
Rapid method to detect
Once MDR-TB is confirmed Individualized MDR-TB regimen (once
MDR (takes around 1–2
susceptibility testing for second-line drugs is
days to detect MDR-TB)
available).

Table2. Potential regimens for the treatment of patients with MDR-TB
Pattern of Drug Suggested Regimen (Daily Unless Otherwise Stated) Duration of Treatment
Resistance (months)
INH (± SM) RIF, PZA, EMB (a fluoroquinolone may strengthen the 6
regimen for patients with extensive disease)
RIF INH, EMB, fluoroquinolones, supplemented with PZA for 12-18
the first 2 months (an Injectable Agents may be included
for the first 2-3 months for patients with extensive disease)
INH, RIF (± SM) Fluoroquinolones, PZA, EMB, Injectable Agents (± 18-24
alternative agent)
INH, RIF (± SM) Fluoroquinolones, PZA, Injectable Agents, and two 24
and EMB alternative agents
INH, RIF (± SM) Fluoroquinolones, EMB, Injectable Agents, and two 24
and PZA alternative agents
Drug Candidates and New Drugs Invented to Treat MDR-TB
New drugs are urgently needed to get to zero deaths, zero new infections, and zero stigma and
suffering from TB. While TB has been curable for decades, existing drugs have to be taken for
months or even years.9 New anti-TB drugs are needed for three main reasons: firstly, to shorten or
otherwise simplify treatment of TB caused by drug-susceptible organisms; secondly, to improve
treatment of drug-resistant TB, and thirdly, to provide more efficient and effective treatment of latent
TB infection.10 Consequently, the landscape of TB drug development has evolved dramatically over
the past ten years, and novel drugs are entering Phase III trials for the treatment of MDR-TB.5 Within
a rational and well-funded infrastructure for conducting multinational large clinical trials, the
importance of the development of new sterilizing drugs that target persistent bacteria and shorten TB
therapy must be intensely promoted by the medical and TB patient advocacy communities.11
Bedaquiline (Diarylquinoline TMC207, R207910)
Bedaquiline [formerly named as TMC20712 or R20791013] is the first new drug from a new drug class
to treat TB to be approved by the United States Food and Drug Administration (FDA) in over 40
years 14, whose chemical structure is seen in Fig. 1.15The drug, to be called Sirturo, was discovered by
scientists at Janssen, the pharmaceuticals unit of Johnson and Johnson, and is the first in a new class
of drugs that aims to treat the drug-resistant strain of the disease.16As a result, the Expert Group
suggested that, as an interim recommendation, bedaquiline may be added to a WHO-recommended
regimen in MDR-TB adult patients under the following conditions: when an effective treatment
regimen containing four second-line drugs in addition to PZA according to WHO recommendations
cannot be designed; and when there is documented evidence of resistance to any fluoroquinolone in
addition to multidrug resistance.4
TMC207 is a first-in-class diary lquinolone compound with a novel mechanism of action 17 and
exhibits excellent activity against drug susceptible, MDR and XDR mycobacterium strains, with no
cross-resistance to current first-line drugs. It appears that TMC207 has greater potency against
mutated drug resistant strains than to fully susceptible isolates, suggesting a unique mechanism of
action. Whilst TMC207-resistant strains have appeared, they remain fully susceptible to other anti-TB
drugs such as RIF, INH, SM and EMB. Diarylquinoline TMC207 seems to act by inhibiting the ATP
synthase, leading to ATP depletion and pH imbalance.12
Figure1.Chemical Structure of bedaquiline (TMC207)

Moreover, diarylquinoline TMC207 has potent bactericidal activity in the established infection in
murine TB model.13Besides, oral once daily administration of TMC207 has bactericidal activity at a
dose of 400 mg when administered as mono-therapy for 7 days in patients with pulmonary TB.
Compared to INH and RIF, the bactericidal activity of 400 mg of TMC207 started later but was of
similar magnitude on days 4 to 7. Serious adverse effects related to the study drug did not occur. 18
TMC207 has bactericidal and sterilizing activity against Mycobacterium tuberculosis (MTB) and
other mycobacterial species but little activity against other bacteria.19
Substitution of RIF, INH or PZA with diarylquinoline TMC207 accelerated activity leading to
complete culture conversion after 2 months of treatment. In particular, the TMC207-INH-PZA and
TMC207-RIF-PZA combinations cleared the lungs of TB in all the mice after two months.
Diarylquinoline TMC207 has been also tested in various combination with the second line drugs
amikacin, PZA, MFX and ethionamide in mice infected with the drug susceptible virulent MTB strain
H37Rv. Diarylquinoline containing regimen were more active than the current recommended regimen
for MDR-TB amikacin-PZA-MFX-ethionamide and culture negativity of the both lungs and spleens
was reached after 2 months of treatment in almost every case.13
As preliminary stage 1 data from a double-blind, placebo-controlled, randomized Phase II trial 19 and
2-years followed up results revealed on the randomized placebo-controlled study 20 confirm the
significant bactericidal activity of TMC207/bedaquiline in patients treated for MDR-TB. In both
studies there is a reduced time to culture conversion and a higher number of culture conversions after
8 weeks of a standard background regimen plus TMC207 in patients with MDR-TB. The compound
was safe and well tolerated over the 8-week treatment period. The emergence of drug resistance was
substantial and may have been reduced by the concurrent administration of bedaquiline.19, 20
Nitroimidazoles (PA-824 and OPC-67683)
Another class of compounds that has been the subject of considerable interest because of their
potential in TB therapy is the nitroimidazoles. Currently, two nitroimidazoles,the nitroimidazo-
oxazine PA824, which is being developed by the TB Alliance, and the dihydroimidazooxazole
OPC67683, which is being developed by Otsuka Pharmaceutical, are in clinical development. This
class of compounds possessed antimicrobial activity. However, when the lead compound (CGI-
17341) was found to be mutagenic in the Ames assay, further development was halted.21
PA-824
PA-824 is a promising new compound, with the chemical name (S)-2-nitro-6-(4-(trifluoromethoxy)
benzyloxy)-6,7-dihydro-5H-imidazo[2,1-b][1,3], as shown on Fig. 2, 22for the treatment of TB that is
currently undergoing human trials. Like its progenitors, metronidazole and CGI-17341, PA-824 is a
pro-drug of the nitroimidazole class, requiring bio-reductive activation of an aromatic nitro group to
exert an anti-tubercular effect. And it was confirmed that resistance to PA-824is most commonly
mediated by loss of a specific glucose-6-phosphate dehydrogenase (FGD1) or its deazaflavin cofactor
F420, which together provide electrons for the reductive activation of this class of molecules.23 PA-824
has substantial bactericidal activity during both the initial and the continuation phases of treatment in
an experimental murine TB model. The minimal effective dose and minimal bactericidal dose were
12.5 mg/kg and 100 mg/kg, respectively. At a dose of 100 mg/kg/day, the bactericidal activity of PA-
824 approaches that of INH at the equipotent dosage of 25 mg/kg/day for humans.24
Figure2. Structural formula of investigational product: PA-824

In the randomized study, PA-824 appeared safe and well tolerated during 14 days of once-daily
dosing in drug-sensitive, sputum smear-positive, adult pulmonary tuberculosis (PTB) patients at
dosages of 200 to 1,200 mg/day. The number of adverse events was low and the severity of events
mostly mild or moderate. PA-824 also showed to have a substantial and linear early bactericidal
activity (EBA) over 14 days comparable to that of the existing first-line TB treatment agents. The
extended EBA of PA-824 suggests that this drug may have sterilizing activity in human PTB and as
such could contribute importantly to the sterilizing and treatment shortening ability of a MDR-TB
treatment regimen.25In another study done on 58 healthy subjects, the safety, tolerability, and
pharmacokinetics of PA-824 were evaluated in two escalating-dose clinical studies, one a single-dose
study and the other a multiple-dose study (up to 7 days of daily dosing). In subjects dosed with PA-
824 in these studies, the drug candidate was well tolerated, with no significant or serious adverse
events.26
The bicyclic nitroimidazole PA-824 has a very complex mechanism of action active against both
replicating and hypoxic, non-replicating MTB. Microarray analysis of the mode of action of PA-824
showed a puzzling mixed effect both on genes responsive to both cell wall inhibition (like INH) and
respiratory poisoning (like cyanide). The aerobic killing mechanism of this drug appears to involve
inhibition of cell wall mycolic acid biosynthesis through unknown molecular mechanism. Whereas in
the case of respiratory poisoning, PA-824 acts directly as nitric oxide (NO) donor, and that NO
release from various PA-824 derivatives correlated well with the anaerobic killing of MTB. Thus, PA-
824 acts as a “suicide bomb” releasing toxic NO within mycobacterial cells and NO possibly reacts
with cytochromes/ cytochrome oxidase to interfere with the electron flow and ATP homeostasis under
hypoxic non-replicating conditions.27
Based on the study done inevaluating 3-drug combinations composed of TMC207, PZA, PA-824,
MFX; and rifapentine, TMC207 plus PZA plus either rifapentine or MFX was the most effective,
curing 100% and 67% of the mice treated, respectively, in 2 months of treatment. Four months of the
first-line regimen did not cure any mice, whereas the combination of TMC207, PA-824, and MFX
cured 50% of the mice treated. The results reveal new building blocks for novel regimens with the
potential to shorten the duration of treatment for both drug-susceptible and drug-resistant TB,
including the combination of TMC207, PZA, PA-824, and a potent fluoroquinolone.28
The murine model for TB has been informative in the development of multi component drug
regimens. In the studies with aerosol infection of mice with TB, PA-824 showed significant
bactericidal activity both alone and when substituted for INH as part of a standard regimen. This
finding was supported by pharmacokinetic data that suggested that PA-824 did not significantly affect
concentrations of RIF, INH and PZA.29In other study, testing of the PA-824, MFX and PZA
combination revealed that the triple combination cured mice more rapidly than the current first-line
regimen components of RIF, INH and PZA. MFX has potent in vitro activity against TB and
improves culture conversion in early TB treatment. 30
OPC-67683
Figure3. Chemical Structure of OPC-67683

A more recently discovered nitroimidazole, OPC67683, is a dihydroimidazo-oxazole under
development by Otsuka Pharmaceutical specifically for the treatment of TB. After undergoing single-
and multiple-dose trials in normal volunteers, the compound is presently being tested in patients in an
EBA trial. OPC67683 has extremely potent in vitro and in vivo activity against MTB.31 OPC-67683,
as its structure shown on Fig. 3 32, is a pro-drug and requires activation by MTB for activity;
experimentally isolated OPC-67683-resistant mycobacteria did not metabolize the compound and a
mutation in the MTB Rv3547 gene (responsible for activating PA-824) among the resistant organisms
suggests that this enzyme is involved in activating OPC-67683. The compound has been shown to
inhibit mycolic acid biosynthesis and kill MTB in vitro.33
In a mouse model of chronic infection, the efficacy of OPC67683 was superior to that of currently
used TB drugs. The effective plasma concentration was 0.1mg/mL, which was achieved with an oral
dose of 0.625 mg/kg, confirming the remarkable in vivo potency of the compound. Besides, OPC-
67683 showed no cross-resistance with any of the currently used anti-TB drugs.34 OPC-67683 showed
dose-dependent killing of drug-tolerant clinical strains of MTB that was superior to INH and
equivalent to RIF, the most strongly sterilizing TB drug. To the extent that findings in the mouse
model indicate potential sterilizing activity in human TB.35The eradication rate of a new regimen
containing OPC-67683 was compared with that of the standard regimen. The OPC-67683-containing
regimen exerted a rapid and consistent reduction during the first 3 months. At 3 months after the start
of treatment, only one colony was detected in one of the six animals; at 4 months, no colonies were
detected in any of the six animals. In contrast, at 6 months for the standard regimen, colonies were
detected in four out of five mice. These results suggest that a new regimen containing OPC-67683
could dramatically reduce the treatment duration by at least 2 months.33
Diamine(SQ-109)
Sixty-nine 1,2-ethylenediamines were re-tested for in vitro activity against MTB H37Rv in a micro-
broth dilution assay. For compound SQ109, its structure shown on Fig. 4 36, the best minimum
inhibitory concentration (MIC) of 1.56µM was determined, selectivity index of 16.7 and 99%
inhibition activity against intracellular bacteria, demonstrated potency in vivo and limited toxicity in
vitro and in vivo. SQ109 was also tested against Erdman and single drug resistant strains of MTB and
demonstrated significant activity: Erdman (0.7µM), ethambutol-resistant (1.4µM in Alamar Blue,
0.99µM in the BACTEC), INH-resistant (1.4µM), RIF-resistant (≤0.7µM). The fact that SQ109 works
against an EMB-resistant strain suggests different specific target, mechanism of action and/or
different activation pathways for SQ109 and EMB.37
Figure4. Chemical Structure of SQ109

The efficacy of SQ109 against MTB was demonstrated through in vitro macrophage model followed
by further testing in an in vivo animal model. Both models were infected with the same MTB strain
H37Rv. SQ109 exhibited both in vitro antimicrobial activity against MTB strain H37Rv grown inside
the host murine macrophage cells (i.e. its ability to penetrate into macrophage phagosome, where
MTB replicates) and in vivo antimicrobial activity on the mouse model inoculated with the H37Rv.
The activity of SQ109 in this regard was comparable to that of INH in the macrophage test system,
but superior over that of EMB.36
SQ109 interacts synergistically with INH and RIF, two of the most important front-line TB drugs.
SQ109 at 0.5 of its MIC demonstrated strong synergistic activity with 0.5 fraction of MIC INH and as
low as 0.1fraction of MIC RIF in inhibition of MTB growth. Additive effects were observed between
SQ109 and SM, but neither synergy nor additive effects were observed with the combination of
SQ109 with EMB or PZA. The synergy between SQ109 and RIF was also demonstrated using RIF-
resistant strains; SQ109 lowered the MIC of RIF for these drug-resistant strains.38 Substitution of the
new diamine antibiotic SQ109 for EMB in a mouse model of chronic TB improved efficacy of
combination drug therapy with first-line TB drugs RIF and INH, with or without PZA: at 8 weeks,
lung bacteria were 1.5log10 lower in SQ109-containing regimens.39
The combination of SQ109 with TMC207 improved an already excellent TMC207 MIC for MTB
H37Rv by 4- to 8-fold, improved the rate of killing of bacteria over the rate of killing by each single
drug, and enhanced the drug post antibiotic effect by 4 h. In no instance, antagonistic activities with
the combination of SQ109 and TMC207 were observed.40 In another study, the two investigational
drugs being developed for the treatment of TB, SQ109 and PNU-100480, combinations were additive
and improved the rate of MTB killing over individual drugs. It showed an overall lack of antagonism
between SQ109 and PNU-100480 in the range of expected therapeutic drug concentrations.41
Oxazolidinone[Linezolid, PNU-100480(Sutezolid) and AZD5847]
The oxazolidinones represent a novel class of antibacterial agents whose mechanism of action appears
to be inhibition of protein synthesis by binding to the 50S ribosomal subunit at a site close to the
site(s) to which chloramphenicol and lincomycin bind but that the oxazolidinones are mechanistically
distinct from these two antimicrobial agents.42 Two oxazolidinones, PNU-100480 and linezolid, have
promising anti-MTB activities in the murine test system.43 AZD5847 also showed anti-mycobacterial
activity.44
Linezolid
Linezolid, its structure shown on Fig. 4 45, is the first oxazolidinone to be developed and introduced in
clinical use. In vitro studies have shown good activity against different species of mycobacteria,
including resistant strains. The linezolid MIC to inhibit the growth of 90% of organisms for MTB is in
the range of 1–2 µg.L-1.46 Linezolid has modest EBA against rapidly dividing tubercle bacilli in
patients with cavitaryPTB during the first 2 days of administration, but little extended EBA.47
Figure5. Structural formula of Linezolid

Linezolid is a valid alternative in patients with MDR-TB. Its anti-mycobacterial activity sharply
increases the efficacy of other second-line therapies. However, the most limiting problem related to
the prolonged use of linezolid in MDR-TB is toxicity, mainly anemia and peripheral neuropathy.48 As
a result, it is recommended to use it with caution, in a dose never exceeding 600 mg, once a day, in
patients with MDR-TB and XDR-TB, who have few other drug options.49 Overall, the available data
suggest that linezolid is a potentially useful drug in treating the significant proportion of MDR-TB
patients in whom second-line regimens fail or who are infected with TB strains with such significant
resistance as not to allow the formulation of an appropriate second-line regimen using recommended
drugs.50
In the study done from 2003-2007, 30 patients received linezolid therapy at a dosage of 600 mg once
daily (2 received intermittent or lower-dose therapy because of low body weight). Of the 30 patients,
22 successfully completed treatment. Among patients who completed treatment, there was no relapse
during a mean follow-up of 1.5 years. All 29 patients with PTB achieved culture conversion, at a
median time of 7 weeks. Five additional patients continued to receive treatment and were tolerating
linezolid well at data censure. Two patients defaulted, and one experienced treatment failure, with an
isolate with the same susceptibility pattern as the initial episode of MDR-TB.51In another study
involving 39 patients with XDR pulmonary tuberculosis who had not had a response to any standard
treatment regimen for 6 months or more, the immediate addition of linezolid at a dose of 600 mg per
day to the ongoing background treatment regimen had a significant beneficial effect on the time to
sputum-culture conversion on solid medium, as compared with the delayed addition of linezolid at the
same dose. During the first 6 months, 34 of the 39 patients (87%) had confirmed culture conversion,
at a median of 76 days. 52 Even though, the role of linezolid in the treatment of MDR-TB and XDR-
TB has been considered controversial, an aggressive, comprehensive management programme using
linezolid along with other drugs can favorably treat significant number of patients with XDR-TB or
pre-XDR-TB.53
PNU-100480 (Sutezolid)
Figure 6.Structure of PNU-100480 (Sutezolid)

Another oxazolidinone, named as PNU-100480, its structure shown on Fig. 6 45, has been
demonstrated to have more potent bactericidal activity in vitro and in a murine TBmodel. Moreover,
the incorporation of PNU-100480 dramatically improved the bactericidal activities of regimens
containing current first-line anti-TB drugs and MFX. For instance, the addition of PNU-100480 (100
mg/kg/day) to the standard regimen of RIF, INH, and PZA resulted in an additional 2.0-log10-unit
reduction in lung CFU counts during the first 2 months of treatment. The combination of PNU-
100480, MFX, and PZA, which doesn’t contain either RIF or INH, was also more active than RIF,
INH, and PZA.54 PNU-100480 also advances further sterilizing activity to the first-line regimen that is
capable of shortening the duration of treatment necessary for cure.55
In the study done on health volunteers, PNU-100480 was well tolerated, showed proportional
increases in exposure to 1000 mg, adequately and predictably absorbed, and exhibited superior
bactericidal activity compared with line zolid, independent of peak drug concentrations.56,57In another
study, the duration of dosing of PNU-100480 was extended to better appreciate potential
oxazolidinone toxicities due to mitochondrial protein synthesis inhibition. No significant untoward
hematologic effects were observed when it was dosed at doses of 600 mg twice daily. Besides, it
shows additive or synergistic activity when it is added to standard doses of PZA.57PNU-100480,
TMC207, PA-824, SQ109, and PZA were examined singly and in various combinations, against
intracellular MTB, using whole blood culture (WBA). Combinations of PNU-100480, TMC207, and
SQ109 were fully additive, whereas those including PA-824 were less than additive or antagonistic.
The most active regimens, including PNU-100480, TMC207, and SQ109, were predicted to have
cumulative activity comparable to standard TB therapy.58 Susceptibility of clinical MTB isolates to
PNU-100480 and linezolid was evaluated. The isolates had various susceptibilities to INH, RIF,
EMB, and SM. The mean MIC for PNU-100480 was 3.2 times lower than that for linezolid.
Therefore, PNU-100480 is a promising candidate to be developed further as an adjunct in the
treatment of MDR-TB and XDR-TB.59
AZD5847
A little further behind in development, AstraZeneca are developing an oxazolidinone, AZD5847.
Healthy volunteer tolerability and pharmacokinetic studies were recently completed but results are not
yet available. A phase II EBA study is in development.60AZD5847, its structure shown on fig. 7 45,
was originally intended as a broad-spectrum antibiotic, but has now been repurposed as an anti-TB
agent.61 It is well recognized that with linezolid, treatment periods longer than 14 days may result in
hematological adverse effects and since treatment for TB is considerably longer than 14 days, the
degree and severity of this off-target activity with the next-generation oxazolidinone agents will be
the key for their development.62
Figure7.Chemical Structure of AZD5847

Pyrrole (LL-3858)
The anti-TB activity of the pyrrole class was first described in 1998. BM212, the most potent pyrrole
derivative studied so far, can be used as a lead for the preparation of new and more efficacious anti-
mycobacterial drugs, with MIC that ranged from 0.7 to 1.5 mg/mL against several strains of MTB
including the resistant strains.63 The mycobacterial target of LL3858, its structure shown on fig. 7 64,
is not yet known having a MIC range of 0.06–0.5 mg/mL that was not affected by resistance to INH
and RIF. Additive activity in combination with first line drugs in the murine model was also
described. The target probably differs from the targets of currently used drugs.65
Figure 8: Chemical Structure of LL3858

Fluoroquinolones (Gatifloxacin and Moxifloxacin)
Of the new compounds being tested for their efficacy in TB treatment, the fluoroquinolones are the
first novel drugs since the development of rifamycins to have been shown to have significant activity
against MTB.66 Currently fluoroquinolones are used as anti-tuberculous agents in MDR-TB and, to a
lesser extent, in the case of severe adverse reactions to the conventional anti-TB regimen.
Fluoroquinolones are not included at present in the first-line treatment of TB, although that might
change in the future, in order to shorten treatment duration. The newer fluoroquinolones, MXF and
gatifloxacin have been shown to exert better activity and are associated with a lower probability of
emergence of resistance.67
Moxifloxacin (MFX)
The excellent in vitro activity of MXF translates into activity in the human host. Moxifloxacin, its
structure shown on fig. 9 64, joins the small number of highly bactericidal anti-TB drugs and may
contribute to the development of more effective regimens.68The results of a comprehensive preclinical
evaluation of the safety of MFX are consistent with those reported for other fluoroquinolones. Most of
the findings (e.g. arthrotoxicity in juvenile animals and CNS toxicity) that have led to restrictions in
the use of quinolones in general have also been observed with MFX.69Besides,MFX has a good EBA
against MTB in patients with drug-susceptible TB. Its extended EBA activity from days 2 to 7, a
putative surrogate marker of sterilizing activity, may be slightly higher than for INH.70
Figure 9: Chemical Structure of Moxifloxacin

In one experimental study, the substitution of MFX for INH in the standard regimen revealed the
dramatic increase in potency and appeared to have the greatest potential to shorten the course of TB
therapy to 4 months or less.71 In contrast, substitution of MFX for EMB in the standard regimen did
not have an effect on 2-months sputum culture status but did result in a higher frequency of negative
cultures at earlier time points among patients with smear-positive PTB. Therefore, MFX has
sterilizing activity, but insufficient activity when used in the manner evaluated in this trial (i.e., added
to INH, RIF, and PZA) to support treatment shortening based on the surrogate marker of 2-months
culture conversion.72
Gatifloxacin
Gatifloxacin, its chemical structure shown on Fig. 10 64, has excellent EBA, only slightly less than for
INH, and greater extended EBA.70Gatifloxacinwas evaluated alone and in combination with
ethionamide, PZA, and EMB. Ethionamide appeared to be the most promising single agent for use in

combination with ratifloxacin. Gatifloxacin-ethionamide-PZA and/or EMB would likely be an
effective regimen for treatment of MDR-TB.73
Figure10. Chemical Structure of Gatifloxacin

In the Randomized Clinical Trial that was done by substituting EMB for new drugs in the standard
regimen, the response at the end of treatment was uniformly high in all regimens, with 95% and 98%
of the patients treated with a thrice-weekly 4-month gatifloxacin and MFX regimens, respectively,
becoming culture negative at the end of treatment, compared to 97% in the standard regimen.74
New Targets Identified for the Development of Anti-TB Drugs
It is reassuring that after many years, a TB drug pipeline is now developing. Moreover, several novel
pathways essential for MTB survival are currently being explored, including the protein kinase G and
coronin 1 pathways, which have potential to serve as novel drug targets for treatment of both drug-
sensitive and drug-resistant TB. Whilst pressing on with the development of drugs and optimized
combination and usage of existing drugs at the “outcome” end of the pipeline, concerted effort is
needed to expand further the portfolio of novel drug targets and to identify novel leads.75
The discovery that focuses on commercially available drugs, such as prescribed for the treatment of
Parkinson’s disease, showed the potential to treat MDR and XDR-TB. These drugs, entacapone and
tolcapone, are predicted to bind to the enzyme InhA and directly inhibit substrate binding. The
prediction is validated by in vitro and InhA kinetic assays using tablets of Comtan, whose active
component is entacapone, with MIC for MTB approximately 260µM. Moreover, kinetic assays
indicate that Comtan inhibits InhA activity by 47.0% at an entacapone concentration of approximately
80µM. So, the active component in Comtan represents a promising lead compound for developing a
new class of anti-tubercular therapeutics with excellent safety profiles.76
Peptide-based antibiotics are attractive both to fundamental research and for their potential therapeutic
applications. They are relatively small molecules, their action is fast and lethal to a large spectrum of
pathogens, and they seem to escape many of the drug resistance mechanisms. Compared to classical
antibiotics, peptides portray a highly modular synthetic antimicrobial system. Unlike classical
antibiotics that must penetrate the target cell to act on it, antimicrobial peptides are believed to kill
target cells by destroying their membrane. Theoretically, this mode of action should severely reduce
microbial resistance and represents, therefore, a promising alternative in the treatment of raging MDR
infectious diseases.77
Mycobacterial persistence which refers to the ability of tubercle bacillus to survive in the face of
chemotherapy and/or immunity is a new approach.78 Gene products involved in mycobacterial
persistence, such as isocitratelyase (ICL),an enzyme essential for the metabolism of fatty acids79;
PcaA, required for cording and mycolic acid cyclopropane ring synthesis in the cell wall of both BCG
and MTB80; RelAMtb (ppGpp synthase), critical for the successful establishment of persistent infection
in mice by altering the expression of antigenic and enzymatic factors that may contribute to successful
latent infection 81; and Rv3133c/DosR, is a transcription factor of the two-component response
regulator class and the primary mediator of a hypoxic signal within MTB, used to control a 48-gene
regulon involved in MTB survival under hypoxic conditions82, have been identified and could be good
targets for development of drugs that target persistent bacilli.
In MTB, the energy production pathways are not well characterized. But, the findings that showed as
PZA acts by disrupting membrane potential and depleting energy in MTB lead to focus on energy
pathway as a drug target.83 Energy production or maintenance is important for the viability of
persistent non-growing tubercle bacilli in vivo. The recent discovery of the highly effective TB drug

TMC207 also highlights the importance of energy production pathways for MTB. It is likely that
energy production pathways, such as the electron transport chain, glycolytic pathways and
fermentation pathways, could be good targets for TB drug development.2
Another target is toxin-antitoxin modules. Inappropriate or uncontrolled expression of the toxin or a
decrease in the expression of antitoxin can cause bacterial cell death.84It is interesting to note that the
MTB genome has recently been found to contain at least 38 toxin-antitoxin modules including three
relBE and nine mazEF loci. RelE and MazF are toxins that cleave mRNA in response to nutritional
stress. Evidence now indicates that these loci provide a control mechanism that helps free-living
prokaryotes cope with nutritional stress.85Hence, the toxin-antitoxin modules are attractive targets in
MTB for designing drugs that either induce the production of the toxin or inhibit the expression of the
antitoxin.2
Essential mycobacterial genes can also be good targets for TB drug development. Systematic analysis
of essential genes by transposon mutagenesis and targeted knockout of specific genes are valuable
approaches to identify essential genes because whose disruption leads to non-viability of the bacilli. 3
Around one-sixth of the total number of genes (614 genes) in MTB, were found to be essential for in
vitro growth.86While 194 genes were demonstrated to be essential for in vivoMTB survival in mice. A
surprisingly large fraction of these genes are unique to mycobacteria and closely related species,
indicating that many of the strategies used by this unusual group of organisms are fundamentally
different from other pathogens.87
It has been demonstrated that the ClpP proteins ofMTB, which are essential for growth in vitro using
genetic means but its activators are effective against mycobacteria, are exciting new drug targets for
exploration using genetic and chemical validation approaches. Targeting the Clp series has the added
advantage that both inhibitors andactivators have the potential to kill the cell. Further work to develop
the acyldepsipeptides (ADEP) activator series or to identify new activators orinhibitors could lead to
the development of new drugs in the long term.88
Challenges in the Development of New Drugs
Along with the socioeconomic and host factors that underlie the serious global burden of TB, a
fundamental problem that hinders more effective TB control is the ability of MTB to persist in the host
and to develop drug resistance, often because of poor adherence to lengthy therapy.10 Despite a
resurgence of TB, development of new drugs to treat the disease has stagnated in the face of
numerous scientific and economic obstacles. Showing of the superiority of new agents constitutes the
most convincing clinical evidence of drug efficacy, but in the case of drug-sensitive disease this may
be infeasible given the high efficacy rates of existing regimens, the need for extended follow-up, and
the large number of participants required supporting statistical conclusions.89
Primarily, overall funding for TB research in general, and drug discovery in particular, remains
alarmingly inadequate. TB research is funded in competition with all other areas of biomedicine and
is clearly not receiving funds commensurate with the global dimension of the disease and the
probability that untreatable forms of TB will become increasingly widespread.90 Besides, the TB drug
market is associated with insufficient profit opportunity or investment return to instigate
pharmaceutical industries to develop new drugs.91Secondly, it is the lack of access to information,
pharmaceutical expertise, compounds, and research tools. There would be great value, for example, in
a publicly accessible database that collected thorough information about screenings of compounds and
about analyses that indicate which targets in MTB appear to be “druggable.” Considering the limited
resources for TB drug development, it is critical to avoid repetitive efforts, particularly multiple
independent journeys to a dead-end.88 However, the molecular mechanisms responsible for
mycobacterial dormancy, persistence, and drug resistance are not yet fully understood.92Thirdly, there
are a number of constraints that have companies from investing in new anti-TB drugs. The research is
expensive, slow and difficult and requires specialized facilities for handling MTB. There are few
animal models that closely mimic the human TB disease. Development time of any anti-TB drug will
be long. In fact minimum six month therapy will require with a follow up period of one year or
more.93Lastly, the challenge of TB drug Research and Development is the long timeline of clinical
trials. Phase II studies for TB drugs typically require at least two years, and pivotal trials a minimum

of three years from beginning patient enrollment to finalized study reports. Furthermore, the fact that
people must be treated with a combination of four drugs, rather than with a single drug, means that to
replace the current regimen with a totally new three- or four-drug regimen by testing the substitution
of one drug at a time into the standard regimen will require not a minimum of six years, but at least
four times six years - over two decades - just for the clinical phase of development.94
FUTURE PERSPECTIVES
A promising new era in TB drug development has begun. It is now critical to consolidate recent
progress and ensure that new drugs/regimens for treatment of all forms of TB are suitably introduced
in countries in a way that guarantees access to best treatments for all those in need and avoids
inappropriate use of new drugs.95 Moreover, one can certainly strive to discover new drugs with
improved efficacy and tolerability and with the ability to be used in new combination therapies to
shorten the current, protracted treatment duration. So, it is important to identify essential TB targets
based on the increased knowledge of the pathogen and the physiology of the disease, to develop
smarter screening assays, and to prepare sets of compounds designed to give improved leads for
antibacterial activities.45 However, it requires the wide involvement of all relevant parties (industry,
academia, drug regulatory agencies, and international policy-making agencies) who must collaborate
effectively to deliver optimal future therapies for TB.96
The emergence of multi-drug-resistant strains of MTB makes the discovery of new molecular
scaffolds a priority, and the current situation even necessitates the re-engineering and repositioning of
some old drug families to achieve effective control.97 In this condition, smaller studies may suffice if
large differences in efficacy between experimental and comparator regimens are likely. Use of
preliminary endpoints may be possible, resulting in accelerated drug approval. In a situation of dire
medical need, large potential benefits may outweigh minor risks. But most important, given the
pressing need for new drugs to treat resistant TB, this approach will bring the promise of new drugs to
an area of major public health concern.89
Finally, ways to shorten clinical trials with new TB drugs should be explored. The evaluation of
surrogate biomarkers that predict the likelihood of relapse, such as serial sputum colony counts and
molecular markers, should be incorporated into clinical trials as much as possible. Validated surrogate
markers will reduce the time it takes to assess the efficacy of new agents.91 Besides, it is important
to develop novel drugs that avoid the manifestation of drug resistance in bacterial cells.
Control programs that implemented have also been less effective than expected in reducing the
occurrence of TB transmission, mainly because patients are not diagnosed and cured quickly
enough.98
CONCLUSION
In the past ten years, the development of anti-TB drugs were extremely increasing and expecting to
improve the current treatment protocol to life saving and optimum status. Consequently, the death and
being infectious resulted from TB will stop or exponentially decrease in near future. However, to
reach this level, it needs hand-to-hand work of different sectors that are responsible for the
development of new drugs. In addition, the research area should look for the potential targets that can
bring paradigm shift in the history of treatment of TB.
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AUTHORS’ BIOGRAPHY
Alemayehu Toma Mena
As Lecturer of Pharmacology in Hawassa University, College of Medicine and
Health Science since May, 2011
Current Research Activities:
Antiglycation activities of extract of Moringa stenopetala leaves in fructose
induced protein glycation
Antidiabetic activities of aqueous ethanol and n-butanol fraction of Moringa
stenopetala leaves in streptozotocin-induced diabetic rats Under submission
Antiinflammatory activity of Moringa stenopetala leaves in carreggen in induced mice.
Evaluation of treatment outcome in antiretroviral therapy in Hawassa Referral Hospital.

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International Journal of Research in Pharmacy and Biosciences

Volume 2, Issue 5,June 2015, PP 1-18

Recent Advances in the Development of Anti-tuberculosis Drugs

*Address for correspondence

2 International Journal of Research in Pharmacy and Biosciences V2 ● I5 ● June 2015

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Figure1.Chemical Structure of bedaquiline (TMC207)

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Figure2. Structural formula of investigational product: PA-824

Figure3. Chemical Structure of OPC-67683

Figure4. Chemical Structure of SQ109

Figure5. Structural formula of Linezolid

Figure 6.Structure of PNU-100480 (Sutezolid)

Figure7.Chemical Structure of AZD5847

Figure 8: Chemical Structure of LL3858

Figure 9: Chemical Structure of Moxifloxacin

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Figure10. Chemical Structure of Gatifloxacin

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