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According to the World Health Organization (WHO), approximately 8.
5% of multidrug-resistant tuberculosis (MDR-TB) cases are extremely drug-resistant (XDR)
.
Meanwhile, only 55% of MDR-TB and 30% of XDR-TB cases are successfully treated
.
In May 2014, during the World Health Assembly in Geneva, a resolution was adopted approving the new post-2015 global tuberculosis strategy
.
The goal is to reduce TB deaths by 95% and reduce incidence by 90% between 2015 and 2035
.
To achieve these ambitious targets, WHO has urged all countries to come forward and collaborate at different levels to develop strategies to address TB and address MDR-TB
.
Even though multiple drugs and vaccines are in various stages of clinical trials, achieving the goals set by the WHO remains a distant dream
.
Mycobacterium tuberculosis (Mtb) is a metabolically versatile bacterium that, when exposed to drugs or stress, is able to switch to an alternative pathway that helps it survive and remain dormant for extended periods of time
.
It's also adept at shutting down its major metabolic pathways but still maintaining rudimentary, minimal survival
.
This ultimate defense mechanism of Mtb is attributed to the mycobacterial regulation of the electron transport chain (ETC)
.
ETCs in mycobacteria include multiple dehydrogenases, an aa3-type cytochrome c oxidase ATPase, leading to ATP synthesis, which is currently being actively studied as a drug target
.
Overview of current treatment regimens Currently, the Centers for Disease Control and Prevention (CDC) has recommended two regimens for the treatment of latent TB infection
.
One is rifamycin-based therapy for 3-4 months, the other is isoniazid (INH) monotherapy, and other drugs include rifapentine and rifampicin
.
In other countries, the duration of treatment is at least six months and includes pyrazinamide (PZA), ethambutol (EMB), and the aforementioned drugs
.
There are two types of drugs that are widely used, depending on the type of infection.
First-line drugs are those used to treat tuberculosis infections that are not drug-resistant
.
These include INH, rifampicin (RIF), PZA and EMB
.
The second class of drugs mainly includes bedaquiline (BDQ) and 4-aminosalicylate, kanamycin, cycloserine, ethionamide, amikacin, capreomycin, thiacetone, fluoride Quinolones
.
These drugs are used to treat M/XDR TB
.
Table 1 lists various drugs in various stages of clinical trials
.
Figure 1.
Different drug modes of action Most anti-TB drugs target one of three pathways: 1) ETC; 2) Cell wall synthesis; 3) Transcription/translation mechanisms; Table 1.
TB drugs in different stages of clinical trials Figure 1.
Different Classes of Drug Molecules First-Line Antituberculosis Drugs 1.
Isoniazid In the early 1950s, the first successfully approved antituberculosis drug, isoniazid, was available for treatment
.
The prodrug isonicotinic acid hydrazide (INH) is activated by the pathogen's catalase-peroxidase to generate a highly reactive isonicotinyl radical
.
These radicals react with NAD+ and NADP+ to form INH-NAD/(P) complexes
.
Many mycobacterial proteins, including dfrA-encoded dihydrofolate reductase (DHFR), are inhibited by INH-NAD/(P) adducts
.
In a preliminary study of InhA, it was observed that some INH-resistant isolates also showed resistance to ethionamide (ETH), even though the source patients had never received ETH treatment
.
Further studies showed that a single base pair mutation in the target gene InhA resulted in the S94A mutation, which was associated with isoniazid resistance
.
This mutation results in reduced binding of the INH-NAD inhibitor to InhA
.
2.
Clofazimine Clofazimine, developed as an anti-tuberculosis drug in 1957, is a phenazine-based molecule responsible for the production of reactive oxygen species and may interfere with the respiratory chain of mycobacteria
.
However, its exact mode of action remains unclear
.
While it showed promising results in an initial screen, it lacked the expected efficacy in a monkey model
.
Therefore, instead of being used as an anti-tuberculosis drug, it was further developed for the treatment of leprosy
.
Although clofazimine treatment has no apparent side effects, individual studies have reported some side effects such as gastric manifestations, diarrhea, skin discoloration, ichthyosis, anorexia, enlarged lymph glands and liver, corneal dryness, and weight loss
.
3.
Rifampicin Rifampicin is a first-line drug and continues to be used for tuberculosis treatment
.
Rifampicin, which is thought to interfere with transcription, has a strong affinity for the beta subunit of RNA polymerase encoded by the rpoB gene
.
4.
Ethambutol Ethambutol is also a first-line drug for the treatment of tuberculosis
.
It has been reported that ethambutol can hinder the synthesis of mycobacterial cell walls and prevent the polymerization of α-galactan by acting on EmbA and EmbB
.
In studies, EMB was found to interfere with cell wall synthesis and plasma membrane integrity
.
It is a competitive inhibitor of the Mtb MurI enzyme, thereby affecting peptidoglycan biosynthesis
.
Presumably, EMB targets multiple enzymes in the Mtb cell wall biosynthetic pathway
.
5.
Pyrazinamide PZA is a revolutionary drug that cuts TB treatment time by months
.
As an analog of nicotinamide, it needs to be converted to pyrazine acid (POA) to be active in the body
.
This conversion occurs due to an enzyme, PZase, found in Mtb
.
Mutations in the gene pncA, which encodes the enzyme PZase, are thought to be the main reason why Mtb acquires resistance to PZA
.
Second-Line Anti-TB Drugs 1.
Bedaquiline In December 2012, the U.
S.
Food and Drug Administration approved TMC-207 (Bedaquiline), a diarylquinoline molecule, for accelerated approval for lung M/XDR TB
.
It is the first new drug for tuberculosis to be approved by the Food and Drug Administration (FDA) since 1971
.
BDQ specifically binds to the C-loop of mycobacterial F-type ATPase
.
BDQ has been reported to inhibit ATP synthesis in actively dividing and latent TB infection, but not in host cells
.
Phase II clinical trials have shown that BDQ has an excellent bactericidal effect, helping to significantly reduce the duration of treatment, even in MDR patients
.
2.
Pratomanib Pratomanib is a prodrug of the nitroimidazole family
.
In dividing bacteria, the drug was observed to interfere with mycolic acid biosynthesis, resulting in the accumulation of hydroxymycolic acid
.
For the efficacy of dormant bacteria, it was found that denitroimidazole, a metabolite of protomanide, produces reactive nitrogen species and depletes ATP in mycobacteria
.
The most common side effects include nerve damage, vomiting, headache, low blood sugar, diarrhea and liver inflammation
.
Limitations of Current Treatment Options All drugs used to treat tuberculosis have serious side effects with long-term use
.
These drugs have a cure rate of more than 95% in clinical trials, but perform much worse in actual treatment regimens
.
The side effects caused by long-term use can reduce the patient's physical and mental ability to withstand the treatment process
.
This morbidity contributes to the development of drug resistance in bacteria while promoting relapse in patients
.
During the incubation period, Mtb forms granulomas in the lungs and can modulate its metabolism, which also affects the success of the treatment process
.
Vaccine Candidate Status BCG was introduced in 1921 and was the only licensed TB vaccine for nearly a century
.
However, the BCG vaccine has serious limitations
.
Although it provides excellent protection against extrapulmonary tuberculosis in younger than 15 years, it provides poor protection against tuberculosis infection in higher age groups
.
Its immune response also varies by population and geography
.
It is estimated that about a quarter of the world's population is a carrier of latent TB infection
.
Therefore, there is a need for a vaccine that can protect adolescents and adults from infection and thereby block the transmission of Mtb
.
There are currently about 16 TB vaccine candidates in various stages of clinical trials
.
Phase III clinical trials are underway for Vaccae™, VPM1002 and MIP
.
The Vaccae™, MIP TB vaccine includes inactivated mycobacterial, whole cell vaccine candidates, while the VPM1002 vaccine candidate consists of live attenuated mycobacteria
.
Tuberculosis vaccines currently under development are classified into live mycobacterial vaccines, subunit vaccines and attenuated mycobacterial vaccines according to the platform used
.
Table 2.
TB vaccines in different trial stages Xiaobian summary Prevention and treatment of TB has always been a major issue in China
.
Controlling TB progression is not a simple medical measure, but requires a strategic and comprehensive implementation of disease prevention, treatment and control steps
.
Despite the development of new anti-tuberculosis drugs, existing combination therapies are clearly insufficient
.
New regimens need to be defined to minimize the risk of drug resistance and drug side effects for patients
.
We still lack a super drug or combination of drugs that can treat all active and dormant TB infections in the shortest time possible
.
To bridge this gap and meet the existing limitations of TB cure, we should pay more attention to research areas such as host-pathogen interactions, structural and functional biology of the Mtb cell envelope, and gain a better understanding of its metabolic pathways
.
References Tuberculosis: Past, present and future of the treatment and drug discovery research https://doi.
org/10.
1016/j.
crphar.
2021.
100037
5% of multidrug-resistant tuberculosis (MDR-TB) cases are extremely drug-resistant (XDR)
.
Meanwhile, only 55% of MDR-TB and 30% of XDR-TB cases are successfully treated
.
In May 2014, during the World Health Assembly in Geneva, a resolution was adopted approving the new post-2015 global tuberculosis strategy
.
The goal is to reduce TB deaths by 95% and reduce incidence by 90% between 2015 and 2035
.
To achieve these ambitious targets, WHO has urged all countries to come forward and collaborate at different levels to develop strategies to address TB and address MDR-TB
.
Even though multiple drugs and vaccines are in various stages of clinical trials, achieving the goals set by the WHO remains a distant dream
.
Mycobacterium tuberculosis (Mtb) is a metabolically versatile bacterium that, when exposed to drugs or stress, is able to switch to an alternative pathway that helps it survive and remain dormant for extended periods of time
.
It's also adept at shutting down its major metabolic pathways but still maintaining rudimentary, minimal survival
.
This ultimate defense mechanism of Mtb is attributed to the mycobacterial regulation of the electron transport chain (ETC)
.
ETCs in mycobacteria include multiple dehydrogenases, an aa3-type cytochrome c oxidase ATPase, leading to ATP synthesis, which is currently being actively studied as a drug target
.
Overview of current treatment regimens Currently, the Centers for Disease Control and Prevention (CDC) has recommended two regimens for the treatment of latent TB infection
.
One is rifamycin-based therapy for 3-4 months, the other is isoniazid (INH) monotherapy, and other drugs include rifapentine and rifampicin
.
In other countries, the duration of treatment is at least six months and includes pyrazinamide (PZA), ethambutol (EMB), and the aforementioned drugs
.
There are two types of drugs that are widely used, depending on the type of infection.
First-line drugs are those used to treat tuberculosis infections that are not drug-resistant
.
These include INH, rifampicin (RIF), PZA and EMB
.
The second class of drugs mainly includes bedaquiline (BDQ) and 4-aminosalicylate, kanamycin, cycloserine, ethionamide, amikacin, capreomycin, thiacetone, fluoride Quinolones
.
These drugs are used to treat M/XDR TB
.
Table 1 lists various drugs in various stages of clinical trials
.
Figure 1.
Different drug modes of action Most anti-TB drugs target one of three pathways: 1) ETC; 2) Cell wall synthesis; 3) Transcription/translation mechanisms; Table 1.
TB drugs in different stages of clinical trials Figure 1.
Different Classes of Drug Molecules First-Line Antituberculosis Drugs 1.
Isoniazid In the early 1950s, the first successfully approved antituberculosis drug, isoniazid, was available for treatment
.
The prodrug isonicotinic acid hydrazide (INH) is activated by the pathogen's catalase-peroxidase to generate a highly reactive isonicotinyl radical
.
These radicals react with NAD+ and NADP+ to form INH-NAD/(P) complexes
.
Many mycobacterial proteins, including dfrA-encoded dihydrofolate reductase (DHFR), are inhibited by INH-NAD/(P) adducts
.
In a preliminary study of InhA, it was observed that some INH-resistant isolates also showed resistance to ethionamide (ETH), even though the source patients had never received ETH treatment
.
Further studies showed that a single base pair mutation in the target gene InhA resulted in the S94A mutation, which was associated with isoniazid resistance
.
This mutation results in reduced binding of the INH-NAD inhibitor to InhA
.
2.
Clofazimine Clofazimine, developed as an anti-tuberculosis drug in 1957, is a phenazine-based molecule responsible for the production of reactive oxygen species and may interfere with the respiratory chain of mycobacteria
.
However, its exact mode of action remains unclear
.
While it showed promising results in an initial screen, it lacked the expected efficacy in a monkey model
.
Therefore, instead of being used as an anti-tuberculosis drug, it was further developed for the treatment of leprosy
.
Although clofazimine treatment has no apparent side effects, individual studies have reported some side effects such as gastric manifestations, diarrhea, skin discoloration, ichthyosis, anorexia, enlarged lymph glands and liver, corneal dryness, and weight loss
.
3.
Rifampicin Rifampicin is a first-line drug and continues to be used for tuberculosis treatment
.
Rifampicin, which is thought to interfere with transcription, has a strong affinity for the beta subunit of RNA polymerase encoded by the rpoB gene
.
4.
Ethambutol Ethambutol is also a first-line drug for the treatment of tuberculosis
.
It has been reported that ethambutol can hinder the synthesis of mycobacterial cell walls and prevent the polymerization of α-galactan by acting on EmbA and EmbB
.
In studies, EMB was found to interfere with cell wall synthesis and plasma membrane integrity
.
It is a competitive inhibitor of the Mtb MurI enzyme, thereby affecting peptidoglycan biosynthesis
.
Presumably, EMB targets multiple enzymes in the Mtb cell wall biosynthetic pathway
.
5.
Pyrazinamide PZA is a revolutionary drug that cuts TB treatment time by months
.
As an analog of nicotinamide, it needs to be converted to pyrazine acid (POA) to be active in the body
.
This conversion occurs due to an enzyme, PZase, found in Mtb
.
Mutations in the gene pncA, which encodes the enzyme PZase, are thought to be the main reason why Mtb acquires resistance to PZA
.
Second-Line Anti-TB Drugs 1.
Bedaquiline In December 2012, the U.
S.
Food and Drug Administration approved TMC-207 (Bedaquiline), a diarylquinoline molecule, for accelerated approval for lung M/XDR TB
.
It is the first new drug for tuberculosis to be approved by the Food and Drug Administration (FDA) since 1971
.
BDQ specifically binds to the C-loop of mycobacterial F-type ATPase
.
BDQ has been reported to inhibit ATP synthesis in actively dividing and latent TB infection, but not in host cells
.
Phase II clinical trials have shown that BDQ has an excellent bactericidal effect, helping to significantly reduce the duration of treatment, even in MDR patients
.
2.
Pratomanib Pratomanib is a prodrug of the nitroimidazole family
.
In dividing bacteria, the drug was observed to interfere with mycolic acid biosynthesis, resulting in the accumulation of hydroxymycolic acid
.
For the efficacy of dormant bacteria, it was found that denitroimidazole, a metabolite of protomanide, produces reactive nitrogen species and depletes ATP in mycobacteria
.
The most common side effects include nerve damage, vomiting, headache, low blood sugar, diarrhea and liver inflammation
.
Limitations of Current Treatment Options All drugs used to treat tuberculosis have serious side effects with long-term use
.
These drugs have a cure rate of more than 95% in clinical trials, but perform much worse in actual treatment regimens
.
The side effects caused by long-term use can reduce the patient's physical and mental ability to withstand the treatment process
.
This morbidity contributes to the development of drug resistance in bacteria while promoting relapse in patients
.
During the incubation period, Mtb forms granulomas in the lungs and can modulate its metabolism, which also affects the success of the treatment process
.
Vaccine Candidate Status BCG was introduced in 1921 and was the only licensed TB vaccine for nearly a century
.
However, the BCG vaccine has serious limitations
.
Although it provides excellent protection against extrapulmonary tuberculosis in younger than 15 years, it provides poor protection against tuberculosis infection in higher age groups
.
Its immune response also varies by population and geography
.
It is estimated that about a quarter of the world's population is a carrier of latent TB infection
.
Therefore, there is a need for a vaccine that can protect adolescents and adults from infection and thereby block the transmission of Mtb
.
There are currently about 16 TB vaccine candidates in various stages of clinical trials
.
Phase III clinical trials are underway for Vaccae™, VPM1002 and MIP
.
The Vaccae™, MIP TB vaccine includes inactivated mycobacterial, whole cell vaccine candidates, while the VPM1002 vaccine candidate consists of live attenuated mycobacteria
.
Tuberculosis vaccines currently under development are classified into live mycobacterial vaccines, subunit vaccines and attenuated mycobacterial vaccines according to the platform used
.
Table 2.
TB vaccines in different trial stages Xiaobian summary Prevention and treatment of TB has always been a major issue in China
.
Controlling TB progression is not a simple medical measure, but requires a strategic and comprehensive implementation of disease prevention, treatment and control steps
.
Despite the development of new anti-tuberculosis drugs, existing combination therapies are clearly insufficient
.
New regimens need to be defined to minimize the risk of drug resistance and drug side effects for patients
.
We still lack a super drug or combination of drugs that can treat all active and dormant TB infections in the shortest time possible
.
To bridge this gap and meet the existing limitations of TB cure, we should pay more attention to research areas such as host-pathogen interactions, structural and functional biology of the Mtb cell envelope, and gain a better understanding of its metabolic pathways
.
References Tuberculosis: Past, present and future of the treatment and drug discovery research https://doi.
org/10.
1016/j.
crphar.
2021.
100037
