Rifampicin and Bedaquiline: New Insights into Treating Tuberculosis

Mengqi Gu

Qibaodwight High School, Minhang, Shanghai, 201101, China

Keywords:

Tuberculosis, Drug Mechanism, Drug Resistance, Modes of Delivery, Drug Economics.

Abstract: Tuberculosis (TB), the Mycobacterium tuberculosis infection, remains as a severe issue around the globe,

killing 1.4 million people in 2019. In this review, rifampicin, a major component of multidrug regimen, and

bedaquiline, a novel drug specifically treats multidrug-resistant TB, are discussed and compared. Rifampicin

(Rif) inhibits RNA polymerase by binding to the β subunit and blocks the elongation of transcription, while

bedaquiline inhibits the F-ATP synthase by preventing c-ring rotation when it binds to the c subunit. However,

multidrug-resistant TB (MDR-TB) has become severe. Mutations can result in key amino acid substitutions

in conformational changes of RNA polymerase, disabling rifampicin to bind. New techniques and possibilities

in the mode of delivery are also explored, as oral rifampicin can be improved by solid self-nanoemulsifying

drug delivery system (S-SNEDDS) and bedaquiline can be improved by inhalation and long-acting injection.

1 INTRODUCTION

1.1 Overview of Tuberculosis (TB)

Tuberculosis (TB) is a bacterial infection caused by

Mycobacterium tuberculosis. It can be spread from

person to person via air. TB usually occurs on the

lungs, but it can take place in kidneys, spine, or brain

as well.

There are two types of TB, latent and active.

People infected by latent TB would not have any

symptoms and would not spread the disease. Latent

TB can only be detected by tuberculin or TB blood

test. While some people can develop active TB from

latent TB the bacteria overcome the immune system

and begin to reproduce. Mycobacterium tuberculosis

can multiply and damage human body issues. Active

TB patients are possibly spread the bacteria. People

with deficient immune system, such as HIV carriers,

are likely to get active TB.

1.2 Mortailities

Up to 2019, the estimated number of people with

latent tuberculosis infection (LTIB) is one-quarter of

the world’s population, who are potentially infectors

of reactivated TB (Cohen, Adam, 2019). In 2019,

According to WHO, 1.2 million children caught TB

due to the difficulty of diagnosing, and 1.4 million

people died in 2019 due to TB. A person has 5-10%

lifetime risk to get active TB when he or she is

infected with bacteria Mycobacterium tuberculosis,

and 45% of active TB infectors (without HIV) would

die.

1.3 Typical Symptoms

Active TB can lead to coughing with or without

blood and mucus, chest pain, loss of weight, fever,

fatigue, night sweats, loss of appetite, etc. (Centers

for Disease Control and Prevention, 2016). Recently,

depression and anxiety were found to be common

among pulmonary tuberculosis (PTB) infectors

(Wang, 2018). Usually, the symptoms are mild for

several months, which result in transmissions to

other people.

1.4 Significance in China and the

World

In China, the incidence of TB has reduced 24% from

2010 to 2019, but China still remains as a high-

burden TB country with 833,000 TB patients in 2019

(WHO China TB treatment).

In 2019, most new TB cases took place in South-

East Asian region (44%), African region (25%), and

Western Pacific (18%) (World Health Organization,

2020).

Gu, M.

Rifampicin and Bedaquiline: New Insights into Treating Tuberculosis.

DOI: 10.5220/0011382200003443

In Proceedings of the 4th International Conference on Biomedical Engineering and Bioinformatics (ICBEB 2022), pages 1179-1187

ISBN: 978-989-758-595-1

1179

1.5 Drugs for Tuberculosis and Their

History

Isoniazid, developed in 1952, is considered as a

highly critical for human medicine by WHO (World

Health Organization, 2015). It was first synthesized

by Meyer and Malley in 2019, while its anti-

tuberculosis activity was discovered in 1945, being

part of the combined drug regimen to solve

streptomycin resistance (Fernandes, 2017). Also in

1952, pyrazinamide was found out to be effective at

tuberculosis (Zhang, 2014). Then, ethambutol was

introduced in 1961. In 1966, Rifampicin was

developed by the Lepetit group as a semisynthetic

drug from Amycolatopsis rifamycinica (Sensi, 1983).

These four drugs consist the combination therapy.

As multidrug-resistant tuberculosis (MDR-TB)

appears, second-line drugs such as cycloserine,

ethionamide, and bedaquiline are applied.

Rifampicin, a widely used first-line drug for TB,

and bedaquiline, the latest drug developed in 2012

for treating MDR-TB, are evaluated in this literature

review to discuss the futural development of anti-TB

drugs.

2 DRUG PHARMOCOLOGY

2.1 Introduction of Rifampicin and

Bedaquiline

Rifampicin is one of the frequently prescribed first-

line drugs for treating TB, while bedaquiline is a

relatively novel drug to treat multidrug-resistant

Tuberculosis (TB), especially patients who are

resistance to rifampicin (Centers for Disease Control

and Prevention, 2016); (PubChem).

This literature review covers from rifampicin and

bedaquiline chemical structure, drug mechanisms,

new insights into the modes of delivery, and drug

economics. This include details of how rifampicin

inhibits bacterial RNA polymerase by blocking

transcription elongation and how bedaquiline

inhibits F-ATP synthase by halting c-ring rotation

are included. This review also discusses how oral

rifampicin is improved by self-nanoemulsifying drug

delivery system (SNEDDS) and how bedaquiline can

be possibly delivered by inhalation and injection.

This review aims to compare rifampicin, a

conventional anti-TB drug, and bedaquiline, a novel

drug, evaluating the futural uses in TB treatment.

2.2 Chemical Structure

Rifampicin is a semi-synthetic drug derived from

rifamycin B (a macrolactam antibiotic), belonging to

ansamycins, as it contains an aliphatic ansa chain

(PubChem). Rifampicin is also a polyketide with

alternating carbonyl groups and methylene groups.

To synthesize rifampicin, aqueous solution of

rifampicin is oxided to rifampicin S. Then, the

rifampicin S quinone structure is reduced with

hydrogen, giving off rifampicin SV. The rifampicin

SV undergoes aminomethylation and turns into 3-

pyrrolidi nomethylrifampicin SV. The product is

oxidized to an enamine and is then hydrolyzed to 3-

formylrifamicin SV, which reacts with 1-amino-4-

methylpiperazine to give off rifampicin.

Bedaquiline, or 1-(6-bromo-2-methoxy-quinolin-

3-yl)-4-dimethylamino-2-naphthalen-1-yl-1-phenyl-

butan-2-ol, is a compound in the diarylquinoline

group (Andries, 2005). Bedaquiline contains a

quinolinic central heterocyclic nucleus with alcohol

and amine side chains, which are responsible for the

antimycobacterial property (Pontali, Emanuele,

2016).

2.3 Mechanism

2.3.1

Rifampicin (Rif) Is A N-Amino-Nʹ-

Methylpiperazine Derivative from

Rifamycin

Figure 1: The chemical structure of rifampicin.

As shown in Figure 1, the blue part indicates the

Ansa bridge and the red part indicates the Napthol

ring. The graph depicts a 2-D chemical structure of

the drug.

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Figure 2: Rif-RNAP cocrystal structure (Campbell,

Elizabeth A, 2001).

As shown in Figure 2, RNAP backbone is

presented by tubes, with transparent molecular

surface. Cyan: β; Pink: β’; white: 𝜔. Rifampicin

shown as CPK atoms, in which carbon is orange,

oxygen is red, nitrogen is blue. The magenta sphere

stands for Mg

ion at the active site.

Rifampicin can inhibit the bacterial RNA

polymerase (RNAP). RNAP, an enzyme catalyzes

the synthesis of mRNA from a DNA template, can

no longer produce mRNA and thus the bacteria

would be unable to produce essential proteins. This

inhibition makes rifampicin a bactericidal drug. The

inhibitor binds to the pocket of RNAP β sub-unit in

the DNA channel or RNA channel (Campbell,

Elizabeth A, 2001)

Rifampicin contains two polar groups on napthol

ring and three polar groups on the ansa bridge (Figure

1), which five form hydrogen bonding with the

binding pocket, and van der Waals association is

formed by hydrophobic side chains around the

napthol ring of rifampicin. Rifampicin thus blocks

the path of RNA elongation when the transcript is 2

or 3 nucleotides long, depending on the phosphate

group of the initiating nucleotide.

Rifampicin approximately doubles the apparent

Michaelis constant of initiating substrate at the

RNAP’s i-site, while not affecting the second

nucleotide binding to i+1 site (McClure, 1978). The

formation of the first phosphodiester bond between

these two nucleotides is catalyzed by RNAP. RNAP

would translocate the 2nt transcript upstream,

causing i+1 site replaces i-site (-1 position), and i-site

nucleotide shifts to -2 position, if the initiating

nucleotide contained a 5’ triphosphate (Campbell,

Elizabeth A, 2001). When the nucleotide is shifted to

-2 position, it would clash sterically with rifampicin.

Therefore, the RNAP is stuck at the position, and

repeatedly produce 2nt transcript every time.

However, if the initiating nucleotide carries a 5’

diphosphate or monophosphate, then the formation

of the first phosphodiester bond would be normal, but

the second phosphodiester bond would fail due to the

steric clash with rifampicin, resulting in 3nt

transcript being repeatedly produced.

To sum up, rifampicin is bactericidal because it

sterically blocks the elongation process of the

transcription, as it binds to the β sub-unit in DNA

or RNA channel of the RNAP.

2.3.2

Bedaquiline (BDQ)

BDQ is a diarylquinoline that treats MDR-TB.

Figure 3: The chemical structure of Bedaquiline.

As shown in Figure 3, bedaquiline is displayed by

a 2-D structure. Each solid line represents

intramolecular bonding, with ends representing

Carbon. Other elements are shown by letters.

Generally, Bedaquiline inhibits the F-ATP

synthase of the Mycobacterium tuberculosis to stop

ATP production. This is done by three mechanisms

of the BDQ.

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Figure 4: General mechanism of bedaquiline (Sarathy, 2019).

As shown in Figure 4, BDQ functions at the cell

membrane and inhibits ATP synthase. No. 1

visualizes BDQ blocking the flow of proton, no. 2

visualizes BDQ stopping c-ring rotation by binding

to ε-subunit, and no. 3 shows BDQ uncoupling

electron transportation.

First, BDQ can halt c-ring rotation by binding to

the c-ring on mycobacterial F-ATP synthase (Preiss,

2015). The c-ring has two c-submits, which have a

cleft between them. The cleft is the binding site of

BDQ, consisting of M. phlei counterparts of D28,

E61, A63, I66 amino acid residues (Preiss, 2015).

The c-ring can be bound by several BDQ molecules

at the same time, and the binding affinity of a single

BDQ molecule would increase if another BDQ

molecule is joined to form complementary binding

(Salifu, 2019). The binding to the c-ring would be

sterically blocked and unable to pass between the

interface of the F-ATP synthase’s a-subunit and c-

ring. The interaction between BDQ and E61 amino

acid residue would prevent the ion exchange, an

essential process for the flow of proton down the

transmembrane pH gradient. Therefore, F-ATP

synthase activity is halted and ATP synthesis is

prevented.

The second target of BDQ is the ε-subunit, is also

related with the c-ring rotation, on the F-ATP

synthase (Biuković, 2012). Mtb ε-subunit connects

c-ring rotation to the ATP formation at the α

headpiece, and it has an interdomain amino acid

interaction network that can deliver information on

c-ring rotation to its C-terminus (Sarathy, 2019). The

C-terminus leads to conformation to contact with

-headpiece and transmits the information.

However, BDQ binds to the Mtb ε-subunit at A10-

W16 amino acid region (Biuković, 2012) and leads

to intra-protein structural changes, damaging the

intra-subunit communication network and thus

inhibiting the Mtb ε-subunit function of connecting

c-ring rotation to the ATP synthesis. The target’s

effect is currently considered as secondary, because,

first, BDQ only has moderate binding to the ε-

subunit (Biuković, 2012), and second, the BDQ

resistance mutations in Mtb only occurs to the c-

subunit (Segala, 2012).

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Figure 5: Chemical structure of analogue of bedaquiline,

TBAJ-876.

As shown in Figure 5, structure is analyzed by 2-

D chemical structure, which can be compared with

bedaquiline structure in Figure 4.

The third mechanism, uncoupling electron

transport from ATP synthesis, is still left

controversial. TBAJ-876, a new BDQ analogue

included in Sarathy et al. research, achieves a similar

antibacterial property of BDQ. The TBAJ-876 has

the same two mechanisms covered previously, but it

doesn’t have BDQ’s uncoupler activity (Sarathy,

2019). This indicates that uncoupler activity is not an

essential part of anti-mycobacterial activity.

3 DRUG-RESISTANT

TUBERCULOSIS

3.1 Significance

The challenge of controlling tuberculosis is now even

furthered due to multidrug-resistant TB (MDR-TB)

and extensively drug-resistant TB (XDR-TB)

(Dheda, 2017). Drug-resistant TB is responsible for

approximately 25% of global TB mortality and is

trickly to cure (World Health Organization, 2020).

Furthermore, the cost of treating MDR-TB is

significant, as 54% of the fund ($2.26 billion out of

$4.2 billion) was spent on the treatment and

diagnosis of MDR-TB in 2020 (World Health

Organization, 2020).

3.2 Rifampicin Resistance

Rifampicin, a major component of multidrug

regimens to treat TB, is found to be ineffective at

MDR-TB. The rifampicin resistance is caused by the

conformational changes of RNA polymerase, as

substitution of the key amino acids can alter the

structure of RNA polymerase. These changes of

amino acids in β subunit of RNAP would prevent

the binding of rifampicin to the enzyme and thus

develop rifampicin resistance (Telenti, 1993).

3.3 Bedaquiline Resistance

Even bedaquiline, the novel drug specific for treating

MDR-TB and XDR-TB, has been reported with

resistance. Due to incomplete treatment, mutations in

the atpE gene can stop BDQ from binding to the c-

subunit of the F-ATP synthase (Koul, 2007). In this

way, BDQ cannot inhibit ATP production and its

bactericidal effect diminishes.

Overall, drug-resistant TB circumstances should

be strictly supervised. Not only conventional

regimen should be improved by optimization, but

also novel drug such as bedaquiline should be further

studied to prevent the rapid loss of this new drug.

4 MODE OF DELIVERY

4.1 Rifampicin (RIF) Delivery

4.1.1

S-SNEDDS

RIF has a poor solubility and bioavailability, while

also causing skin microbiome modification and

hepatotoxicity (Hakkimane, 2018). In the acidic

system, RIF is hydrolyzed to 3-formylrifamycin SV

and 1-amino-4-methylpiperazine and in alkaline

environment, it is autoxidized into oxidized species

like inactive rifampicin quione (Mishra, 2019). To

solve this problem, the self-nanoemulsifying drug

delivery system (SNEDDS), a lipid-based

nanocarrier, is suggested, since it can improve

rifampicin’s solubility, bioavailblity, and stability

(Verma, 2015). SNEDDS can possibly increase the

penetration of nanocarrier-based drug through the

intestinal mucosa (Hussain, 2019).

Recently, solidified SNEDDS (S-SNEDDS) was

developed from the liquid SNEDDS to improve oral

bioavailability. It is also an effective dispersible

nanoemulsion when contacting with gastric fluid

(Hussain, 2019). In the experiment, placebo

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SNEDDS performed a stable nano-emulsification

after reconstituting with distilled water and an

improved permeation across rat intestinal membrane

(Hussain, 2019). The dissolution rate was also

promoted, as the solid adsorbent increased the

specific surface area.

Generally speaking, rifampicin’s solubility,

bioavailability, and the oral penetration through

intestinal mucosal membrane are likely to be

improved by SNEDDS, while the S-SNEDDS

furthers the benefits of this delivery system.

4.2 Bedaquiline (BDQ) Delivery

4.2.1 Oral Tablets

Currently, BDQ is delivered by oral as tablets, but

since it is a novel drug, the mode of delivery is still

left for exploration. Two possible routes, inhalation

and injection, are discussed below.

4.2.2 Inhalation Delivery

Since TB is a disease in lungs, inhalation might be a

target-specific method, with short duration treatment

and minimize the side effects caused by oral delivery

(Rawal, 2018). The delivery is carried out by

nanoparticles (NPs), which are small enough to be

easily uptaken by alveolar macrophages (Paranjpe,

2014).

BDQ NPs in the study shows positively charged

behavior, facilitating high uptake by the negatively

charged sialic acid on alveolar macrophages (Rawal,

2018). No toxicity on cells or organs was shown by

the NP formulation, and NP formulation is likely to

reduce BDQ dosing frequency comparing to dry

powder inhalation (DPI) and oral delivery (Rawal,

2018).

4.2.3 Injectable Delivery by Long-Acting

Injectable (LAI) Formulations

LAI formulations are considered to enhance the

latent tuberculosis infection (LTBI) completion rates

(Swindells, 2018). LAI formulations could also be

more convenient for children than oral daily

formulations.

To be suitable for LAI, the antibiotic typically has

a low aqueous solubilty, which prevents immediate

dissolution and release of the drug, and a relatively

long pharmacokinetic (PK) elimination half-life

(Park, 2013). BDQ, which has a low minimum

inhibitory concentration and a long half-life, would

probably fits the standards (Kaushik, 2019).

LAI formulations for BDQ can help to overcome

poor oral bioavailability, ease the toxicity of BDQ,

and reduce drug to drug interactions (Kaushik, 2019).

In the study of Kaushik et al., a single dose of long-

acting BDQ resulted in apparent duration of

bactericidal property, which could last more than 12

weeks, meaning that the plasma BDQ levels were

above the MIC for at least 12 weeks after

administration. The bactericidal activity of a single

injection during those 12 weeks was also

significantly more active than the daily oral regimen

of same total dose (Kaushik, 2019). This would make

possible that two injections of long-acting BDQ,

which are administrated 4 weeks apart, can result in

the same effect as the WHO-recommended LTBI

treatment regimens.

5 DRUG ECONOMICS

5.1 Rifampicin

Before figuring out the medical cost, we have to

know the optimum dosage of the drug. Usually,

rifampicin is given 10mg/kg (or 600mg) once a day

due to a consideration of economics and toxicity

(Van Ingen, 2011). However, this dosage might be

suboptimal and result in a lower end on the dose-

response curve (Boeree, 2015), which is partially

responsible for the MDR-TB (Hu, 2015). A new

research suggested that 32mg/kg of daily rifampicin

is safe and effective at severely-ill patients (Seijger,

2019).

According to Global Drug facility, the price of

600mg daily rifampicin for 25 days is ranged from

$5.44 to $14.85. If we apply the new dosage,

32mg/kg daily dosage, the price would be higher, and

even tripled.

To treat active TB, rifampicin is taken with

ethambutol daily for 2 months and then a

combination of rifampicin and isoniazid is

implemented for 7 months (Centers for Disease

Control and Prevention, 2020). This means that

rifampicin alone would be taken each day for 9

months in total, which is already expensive. For

latent TB infection, rifampicin is used daily for 7

months in total.

5.2 Bedaquiline

The price of BDQ for a month, comparing to

rifampicin, is even higher. The cost of BDQ for 6

months is around $900, $3,000, and $30,000 in low-

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income, middle-income, and high-income countries

respectively (World Health Organization, 2016).

6 CONCLUSION

6.1 Summary

To sum up, rifampicin and bedaquiline are both

bactericidal, while rifampicin inhibits transcription

and bedaquiline inhibits the ATP synthesis. As

rifampicin is a major component in the most common

multidrug regimen, the rifampicin resistance has

been severe (Dorman, 2018). In 2015, 125,000

rifampicin-resistant were identified while the

estimated number was 580,000 (World Health

Organization, 2016). To mitigate the resistance, a

maximum rifampicin dosage was found to be

32mg/kg daily (Seijger, 2019), but an optimum

dosage should be further investigated. The increased

dosage might lead to an even higher medical cost of

rifampicin. In contrast, since bedaquiline is novel and

has a special mechanism of inhibiting ATP synthesis,

less resistance to the drug has appeared (Preiss,

2015). Bedaquiline resistance should be studied and

regulated strictly because it is one of the few

treatments for XDR-TB (Karmakar, 2019). A

limitation of BDQ is that it can only be used for

MDR-TB, and it is also expensive ($900 for 6

months treatment in low-income areas) for

underdeveloped countries to afford (World Health

Organization, 2019). Bedaquiline is a novel drug

with significant potential, as it has the opportunity to

be administrated by inhalation or long-acting

injection. BDQ can directly reach lungs, the site of

TB injection, by inhalation method (Rawal, 2018),

while long-acting injection enables BDQ to be

administrated once a week, improving the

completion rate (Kaushik, 2019).

6.2 Evaluation and Future Work

Although oral rifampicin is already mature, it can be

improved by new delivery systems such as

SNEDDS, so further investigation is still in need.

Generally speaking, rifampicin is currently

irreplaceable, but it requires solutions to the drug

resistance and new strategies to improve its quality,

while bedaquiline is a highly critical for treating

MDR-TB and XDR-TB, and its delivery methods are

still left for explorations.

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