Biology

Multidrug Resistant Tuberculosis: What is Multidrug-Resistance? Strategies against multidrug-resistance tuberculosis

Seo Young Hong La Canada High School, Grade 12 United States

UCI x GATI BEAM

[email protected]

1. ABSTRACT

Multidrug-resistant (MDR) bacteria strains are one of the most dangerous threats of the century. The World Health Organization (WHO) states that tuberculosis (TB) is within the top 10 leading causes of death, and with the rise of MDR, it will rise higher on the list.1 According to the Center for Disease Control and Prevention (CDC)’s antimicrobial resistance threats report in 2019, there were approximately 2.8 million reports of MDR bacteria infections in the United States.2 Of those, 35,000 cases resulted in death. MDR TB, one of the most widespread strains in the United States today, is included in CDC’s serious threat list.2 This literary review addresses the various antibiotic resistance (AR) in MDR TB and prevention methods against antibiotic resistant (AR) strains.

1.1 HISTORY OF ANTIBIOTICS AND MDR

In 1909, Paul Ehrlich, a German physician, discovered that arsphenamine was an effective syphilis treatment. In 1928, Alexander Fleming accidentally discovered the beneficial use of the fungus Penicillium notatum. This unforeseen discovery has saved about 80,000,000 to 200,000,000 lives.3 Since the discovery of modern antibiotics, scientists have encountered many cases of AR. AR is the ability of a bacteria to become immune to the effects of antibiotics. This causes an increase in Minimum Inhibitory Concentration (MIC), the minimum amount of a drug that prevents the growth of a certain bacteria. Unfortunately, as new antibiotic treatments are being created and used, there are more cases of AR.

1.2 PURPOSE AND REGULATION OF ANTIBIOTICS

Antibiotics prevent food-animal disease, enhance food-animal growth, and kill bacteria that have infected humans. The overuse of antibiotics is one of the leading causes of the increase in number of MDR strains. Countries have followed WHO advice on putting restrictions on antibiotic use for non-medical reasons to decrease AR.4 While the problem in developed countries is over-prescription and incorrect prescription of antibiotics, underdeveloped countries have easy accessibility to a limited variety of antibiotics, creating larger resistant strains to those specific groups of antibiotics.

Poor regulation and easily accessible antibiotics amplify the effects of natural selection, with resistant strains that have greater fitness surviving and reproducing more. There has been an exponential increase in the number of resistant strains and the number of antibiotics the bacteria grow resistant to. AR is more prevalent in underdeveloped countries due to decreased regulation of antibiotics.5 Another factor the spread of bacteria can be attributed to is globalisation. Increase in activities such as travel and trade can cause resistance strains to spread to other parts of the world.

2. TUBERCULOSIS

Mycobacterium tuberculosis is an airborne infectious bacterial disease.6 In 2012, there were about 450,000 cases and 170,000 deaths worldwide from MDR TB7; in 2016, about 490,000 cases and 240,000 deaths.8 It is common for MDR TB to be resistant to isoniazid and rifampin, the two most potent TB drugs. Extensively drug-resistant (XDR) TB is resistant to a larger number of TB antibiotics, including isoniazid, rifampin, and fluoroquinolone. Each strain can be resistant to different variations of anti-TB drugs, including first line drugs, second line drugs, and even the newly developed TB drugs being formed as older antibiotics become less effective.

Patients infected by an XDR strain of TB have fewer effective treatment options. Due to this, patients with weaker immune systems are especially at risk of developing a more serious case of TB once infected. Because there are no effective treatment options for these immunocompromised patients, they cannot fight off the bacteria. Therefore, there is a higher mortality rate among these patients.

Resistant strains of TB form if patients do not fully complete their treatment plans or when the drugs are not effective. They can also form if healthcare providers prescribe the wrong treatment, inadequate dose, or incorrect length of treatment. To reduce the risk of infection of resistant strains of TB, patients should take their medication regularly, take all of their medication as prescribed, make an effort to prevent reinfection, take precautions when visiting countries known to commonly have resistant strains, and prevent contact with patients of resistant strains of TB.9

The percentage of MDR TB present in new versus reinfection cases are different depending on the country. However, the ratio in general is about 2:5. Such countries with frequent cases of MDR TB are China, India, and the Russian Federation. About 6.2% of the cases from these countries were XDR TB.10 Patients of resistant strains of bacteria should quarantine themselves to prevent the spread of AR TB. The patient should also consistently take all of their medications as prescribed to eliminate the strain of AR TB that infected them.

2.1. MECHANISMS OF RESISTANCE

Some of the mechanisms bacteria use to resist antibiotics include altering the antibiotic target site, decreasing uptake, creating bypass pathways, and enzymatic inactivation or modification of the antibiotic. By altering the antibiotic target site, the bacteria protects itself from the antibiotic. This resistance mechanism prevents the antibiotic from inhibiting the target site’s activity since it cannot attach to the enzyme. Bacteria have two ways of decreasing the uptake of antibiotics. One is to decrease the penetration of the antibiotic. Another is to increase efflux by creating ATP-powered transport pumps to continually pump out antibiotics faster than the flow rate inward.

Bacteria can also prevent the effects of the antibiotic by creating bypass pathways using alternative targets resistant to the antibiotic’s inhibition, or producing enzymes to change the antibiotic so that while remaining functional, it is unable to reach its target. Bacterial enzymes are also able to inactivate the antibiotic completely.11

Since MDR TB is usually resistant to the two most potent antibiotics given to patients to treat TB, effective antibiotics left to treat MDR TB are limited and expensive. Combinations of drugs may also cause the MDR strain of TB to develop into an XDR strain of TB. Increased resistance to a greater range of antibiotics reduces the number of antibiotics left to treat TB. There have been 117 countries reported to have cases of XDR TB as of 2018.10

WHO recommends that health departments speed up the detection and improve treatment outcomes for resistant strains of TB through novel rapid diagnostic tests. WHO suggests the following as solutions to control resistant strains of TB: cure patients during the first infection, provide access to diagnosis, ensure adequate infection control in facilities where treatment takes place, and ensure the appropriate use of recommended second-line drugs.10

2.1.1. ACQUIRED RESISTANCE

Bacteria gain resistance mainly through acquired resistance: mutations or horizontal gene transfer mediated by phages, plasmids, or transposon elements. However, mutations from selective pressure of antibiotic use are the leading cause of resistance in TB. Deriving from Darwin’s theory of evolution, bacteria with multiple resistance genes are favored as antibiotics are overused, causing an evolution of bacteria resistant to a broader range of antibiotics.

(Figure 1. Possible Correlation between Citric Acid Cycle and AR. Author’s own image made with Biorender, referencing https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3982203/)

There is a potential correlation between the citric acid cycle and mutations in bacteria that cause the development of AR (Figure 1). When an antibiotic interacts with its target, it triggers a reaction in the electron transport chain that oxidizes the NADH created in the citric acid cycle. The disruption in the electron transport chain causes an increased production of superoxides that destroys the iron-sulfur clusters in Complex II. The destruction then releases the irons to oxidize the Fenton reaction. The Fenton reaction creates hydroxyl radicals that damage the nucleic acids, proteins, and lipids and cause apoptosis. However, if the radicals fail to harm the bacteria, they could promote mutagenesis that will create mutations to recognize and cause the bacteria to be resistant to the antibiotic that triggered this process.12

2.1.2. TARGET ALTERATION

One mechanism of resistance in TB is target alteration. By changing the antibiotics’ target sites, TB can become resistant because the antibiotic is unable to bind to the target site on the bacteria and initiate apoptosis. The erm37 gene directly uses this mechanism. In a study, the BCG vaccine was used because the target site mimics the structure of that in TB. The anti-TB drugs bind to a site on the ribosomal RNA to inhibit the translocation of peptidyl-tRNA. This inhibits protein synthesis and leads to apoptosis. However, the erm37 gene can alter the ribosomal structures by methylating the 23S ribosomal RNA. By doing so, the target site on the ribosomal structures change, and the anti-TB drugs cannot bind to the site. The inability to bind causes resistance to antibiotics in the mycobacteria.12

2.1.3. TARGET MIMICRY

Another mechanism of resistance used by TB is target mimicry. This resistance pathway is an intrinsic resistance as the bacteria produces the protein that mimics the target site, MfpA. Fluoroquinolone is an antibiotic that kills the bacteria by binding to DNA gyrase or topoisomerase. This causes inhibition of DNA replication, transcription, and repair as the absence of gyrase and topoisomerase causes the DNA to remain coiled and experience steric hindrance. Eventually, the DNA will degrade, causing apoptosis. A study on Mycobacterium smegmatis and Mycobacterium Bovis found a correlation between MfpA and fluoroquinolone resistance. Since MfpA’s structure is closely related to that of DNA, fluoroquinolones are said to mistake it for the target site, bind to it, and free the real bacterial DNA from the antibiotic, creating resistance in the bacteria.12

2.1.4. DRUG MODIFICATION

Mycobacteria can also inactivate the antibiotics by modifying it. Aminoglycosides are widely used TB antibiotics. Researchers presume that these antibiotics work to treat TB by inhibiting protein synthesis, thus killing the bacterial cell. TB resistant to this class of antibiotics secrete the enhanced intracellular survival (Eis) protein. This protein is usually secreted by TB to acetylate the MKP7 on the infected macrophage’s cytosol, suppressing the host’s immune responses to the bacterial infection.

In a study where aminoglycoside resistance determinants were screened, researchers found a mutation in the promoter region of Eis, which increased Eis transcription by 180-fold.12 In vitro studies demonstrated that Eis allows the bacteria to resist aminoglycosides by acetylating amine groups on the antibiotic using acetyl-CoA as the acetyl donor. Recent studies show that Eis also has the ability to acetylate capreomycin, an antibiotic used to treat MDR TB.12 These findings indicate that TB resistance is evolving, and there are even fewer antibiotics now available to use against TB and MDR TB. Therefore, it is critical to have more stringent regulations and better monitor its usage and distribution when new antibiotics are designed to better counter the resistance.

2.1.5. DRUG DEGRADATION

TB can resist antibiotics by degrading them with hydrolases. β-lactams bind and inhibit penicillin-binding proteins (PBP), disrupting cell wall synthesis, leading to cell death. Since it has been proven that β-lactams can bind to all of TB’s major PBPs at clinically achievable concentrations, it is concluded that target accessibility, not target affinity, is the cause of AR.

The mycobacteria use β-lactamases to hydrolyse the β-lactam rings of drugs, disabling the antibiotic. Although β-lactamases are less effective in mycobacteria than in other pathogenic bacteria, the bacteria’s impermeable cell wall causes slow penetration. The slow penetration allows the low β-lactamase activity to sufficiently protect the bacteria from β-lactams.

BlaC is the most critical β-lactamase in TB and is widely studied. BlaC is a vital enzyme in TB resistance to antibiotics as it has a broad substrate specificity, possibly due to its large and flexible substrate binding site. This allows it to bind to many different antibiotics, even those known to be resistant to β-lactamases. Even lactamase inhibitors such as clavulanic acid cannot inhibit BlaC. When β-lactams are absent in the bacteria, BlaI, a winged-helix transcription repressor, forms homodimers that bind the prompter of blaC. When β-lactams are detected, BlaI dissociates from its DNA binding site, which derepresses the BlaC transcription so that BlaC can be produced to fight off the antibiotics.12

2.1.6. DRUG EFFLUX

Drug efflux is another resistance mechanism used by bacteria to prevent the antibiotic reaching its target site. Instead of deactivating the antibiotic or changing itself to make the antibiotic ineffective, bacteria can use efflux pumps to push the antibiotic out of its cytoplasm. The normal function of an efflux pump is to transport nutrients, wastes, toxins, or signaling molecules across the cell wall.

There are at least 18 identified transporters that are related to AR. Most transporters are used for other mechanisms within the bacterial cell, but once antibiotics are detected, it causes these pumps to function as drug efflux transporters. Detection of the drug causes increased transcription of the transporters in order to keep the drug away from the target site effectively. Tap, one of the transporters that can perform drug efflux in AR TB, can pump out aminoglycosides, spectinomycin, tetracycline, and PAS.12

 

3. PREVENTION ENDORSED BY CDC

To decrease the rate of AR and the number of deaths caused by MDR bacteria, it is essential to address the issues of incorrect prescriptions, agricultural uses, and easy accessibility of antibiotics.

CDC’s national action plan to combat antibiotic-resistant bacteria (CARB) started in 2015, and called for a 50% decrease in the prescription of antibiotics by 2020.13 In 2015, healthcare providers prescribed 269.4 million antibiotic prescriptions.14 In 2018, 249.8 million.15 Observing the rate of change, it was unlikely that CDC would be reaching their goals by the end of 2020; however, the downward trend suggests a promising decrease in antibiotic usage, which will in turn lead to a decrease in the rate of AR.

CDC defines four major points to prevent AR. First, preventing infections entirely will prevent AR by allowing fewer prescriptions of antibiotics. Furthermore, AR bacteria would not be spread to areas where there were initially no resistant strains. Secondly, tracking those infected with resistant bacteria would lessen the spread of AR bacteria. Thirdly, antibiotic prescription management may be one of the most important ways to reduce AR in bacteria. The problem of AR is exacerbated by over-prescription and incorrect prescription of antibiotics. Management of prescription in the animal food industry and human disease prevention will dramatically decrease the uprising of new resistant strains of bacteria because most antibiotic use is unnecessary. Lastly, developing new drugs and diagnostic tests could allow us to slow down the evolution of bacteria. This will give researchers more time to find new antibiotics to eliminate resistant strains and cure AR bacterial infections. Diagnostic tests would allow us to track the development of resistance and administer the right antibiotic to the patient.16

There are also ways that the general public can help with fighting off AR. Patients prescribed with antibiotics should take the medication as prescribed, not skip doses, not save antibiotics, not take the medication for other purposes, and not take antibiotics prescribed for someone else. Health professionals prescribe antibiotics for specific infections, and taking them for other infections could create a resistance strain. If the antibiotic doses are skipped, the bacteria can evolve and grow resistance to the prescribed medications. Other non-medical ways that people who are not infected can fight against AR are practicing good hygiene and cooking food suitably.17

The FDA is also doing its part in combating AR. The FDA’s scientists have been approving new antibiotics for use in patients with limited or no other treatment options due to infection of MDR, XDR, or pan-drug resistant (PDR) strains of bacteria. They have been labeling regulations addressing the proper use of antibiotics to help healthcare professionals fight AR. They have also partnered with the CDC to create media awareness of antibiotic awareness so that the general public can understand the effects of AR and do their part in combating it. Lastly, the FDA has been encouraging the development of new antibiotics and has organized workshops to address the development of new antibiotics that treat the infections from resistant strains of bacteria.16

Other groups like the National Institute of Allergies and Infectious Diseases (NIAID) are supporting research on vaccines for bacterial infections so that there could be a way to decrease the number of infections, and thus the spread and creation of resistant strains of bacteria.18

There are also ways that policymakers can help control the spread of AR. AR is a significant problem that needs to be handled with a national action plan that improves surveillance of AR infections, strengthens the policies that implement prevention and control of infections, regulates and promotes appropriate use of medications, and makes information available on the impacts of AR.15

There are many methods described by researchers to introduce second-line drugs in TB programs to overcome MDR TB. Considering MDR TB as a public health emergency would allow for growth in TB control programs. To prevent further development in AR strains, current ineffective TB programs that have been using second-line drugs should be changed to create a proper TB control program. However, even with plans created to fight off MDR TB with second-line drugs through TB programs, these plans are not guaranteed because most second-line drugs are expensive and complex. Furthermore, with many of the MDR TB patients located in impoverished countries, the currently existing programs are unable to provide sufficient treatments. In conclusion, the first and foremost step to fight MDR TB is reducing poverty risk factors such as malnutrition and sanitation.19

4. CONCLUSION

Multidrug-resistant (MDR) bacteria strains, including the widespread strain MDR TB, are one of the most dangerous threats of the century. While the problem in developed countries is over-prescription and incorrect prescription of antibiotics, underdeveloped countries have easy accessibility to a limited variety of antibiotics, creating larger resistant strains to those specific groups of antibiotics. Although Bacille Calmette-Guérin (BCG) is an available vaccine for TB, it is an ineffective treatment because the mechanism behind how TB interacts with the body is not as well known. Therefore, when a new, more effective vaccine is developed, it is essential to ensure the public becomes more aware of the importance of getting vaccinated for TB to lessen the infection rate.

Bacteria use acquired resistance, target alteration, target mimicry, drug modification, drug degradation, and drug efflux to overcome antibiotics.

The effects of AR bacteria can be slowed and stopped with essential and straightforward changes if action is now taken. There are different ways that the general public, health professionals, policymakers and researchers can help to fight AR bacteria, medical and non-medical. In particular, management of prescription in the animal food industry and human disease prevention will dramatically decrease the uprising of new resistant strains of bacteria because most antibiotic use is unnecessary.

To help scientists have more time in finding new, more potent antibiotics that could eliminate resistant strains and cure AR bacterial infection, everyone should help in funding the research for developing new drugs and diagnostic tests that could allow the slowing of the evolution of bacteria.

However, the first and foremost step to fight MDR TB should be reducing poverty risk factors such as malnutrition and sanitation so as to prevent people from contracting these infections in the first place.

ACKNOWLEDGEMENTS

I would like to thank UCI x GATI BEAM for giving me the opportunity and resources to write this paper.

Thank you to Jong Hyun Choi for being patient in guiding me through the process of writing the paper as my publication mentor.

Thank you to my uncle, Seok Won Kim PhD., for reviewing and giving me advice on my literature review.

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About the author 

Seo Young Hong is a senior at La Canada High School who has a strong interest in Biology. She loves doing volunteer service and staying active through different kinds of sports and physical activities.

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