Antimicrobial Resistance in Mycobacterium Tuberculosis: A Review

The dangers of tuberculosis (TB) still form a reality for a large segment of the global population, as it cannot be called a “disease of the past,” unlike bubonic plague, for instance. TB continues to represent a growing threat, as around 2 million people become its victims annually (Gengenbacher and Kaufmann, 2012, p. 514). Despite the considerable amount of research directed at ameliorating ways to diagnose and treat TB all around the world and the substantial financing, new obstacles emerge that hinder the hopes for the disease’s eradication. Antimicrobial resistance is a factor that steadily nullifies the efforts put into the attempts to triumph over TB. This phenomenon may be defined as the natural or acquired ability of the disease’s causative agent to maintain vital activity when exposed to medication (Fong et al., 2018). Investigating antimicrobial resistance is a means to possibly enhance the efficacy and overall performance of drugs directed at treating TB.

Antimicrobial resistance makes TB a deadly infectious disease, even in developed occidental countries. Nevertheless, the majority of 1.8 million deaths caused by TB occur in developing countries, which is aggravated by the fact that the treatment of cases caused by drug-resistant Mycobacterium tuberculosis (M. tuberculosis) strains requires second-line drugs. The reasons for the formation of drug resistance are different and may vary from medical errors in the development of treatment regimens to the lack of funding and the use of less effective, cheaper drugs. The gravity of the situation is illustrated by the discovery of streptomycin, which was effective only during the first months of TB treatment. An array of different ineffective drugs followed streptomycin until rifampicin was introduced and shortened the treatment duration sufficiently. Thus, while a TB vaccine is unavailable, the need for effective medication is especially heightened.

Understanding the mechanisms of antimicrobial resistance in M. tuberculosis is another crucial element in limiting the spread of new unsusceptible strains. “Antimicrobial Resistance in Mycobacterium Tuberculosis: Mechanistic and Evolutionary Perspectives” is an article that investigates in-depth the process under consideration (Gygli et al., 2017). A variety of mycobacterial species are involved in studying the processes that allow M. tuberculosis to stay vital under drug exposure: they are favored for the procedure because of their faster growth and biosafety requirements. The differences in genome between these mycobacteria (M. smegmatis, for instance) species and M. tuberculosis restrain the extent to which the research results may apply to the latter.

The resistance that M. tuberculosis possesses may be explained by several inherent characteristics of mycobacterial cell walls. First of all, mycobacterial cell walls are thicker and hydrophobic due to their composition rich in lipids and mycolic acids, preventing the infiltration of hydrophilic compounds. Thus, the success of M. tuberculosis as a pathogen may be partially contributed to the way its walls function and their structure (Maitra et al., 2019). Secondly, the low number of porins, a membrane’s channels, worsens a cell’s diffusion capacity. Membrane fluidity, the facility with which molecules move in the membrane environment, is quite low in M. smegmatis – another contributing factor to drug resistance. Hence, the features of mycobacterial cell walls that complicate the spreading of antibiotic molecules serve as a specific basis for antimicrobial resistance in TB.

Cell wall penetration is only the first obstacle that antibiotic molecules encounter on their way, as several inactivation mechanisms are present in M. tuberculosis cells. The first is enzymatic cleavage, a process of breaking the peptide bonds between amino acids in proteins that renders drugs ineffective. Chemical modification, for instance, methylation, is another mechanism that is performed by enhanced intracellular survival protein (Eis). Eis is known to inactivate some of the injectable second-line drugs. Besides the described inherent mechanisms of drug resistance, new ones continue to emerge, complicating the process of finding an effective treatment even further.

The importance of investigating efflux systems for developing drug resistance in M. tuberculosis becomes an increasingly noticeable, although controversial concept. An efflux system, a system of pumps that removes unwanted toxic substances from a sale, is potentially a significant contributor to antimicrobial resistance, especially to isoniazid, an antibiotic used for TB treatment. Efflux pumps may be crucial to understanding macrophage infection, as macrophage constitutes the host organism’s primary defense against pathogens. Gene expression of efflux pumps in M. tuberculosis can be prompted by several antituberculous drugs, a result that is invalidated by the absence of correlation between strains. Nonetheless, the efflux system, seemingly, participates in developing drug resistance, and its inhibitors may be incorporated into lowering the concentration of chemicals that prevents bacterial growth in antituberculous medication.

The discussed above inherent drug resistance constitutes a smaller percentage, conceding to the acquired type. Acquired drug resistance may be considered a consequence of chromosomal mutations that stem from several various mechanisms, resulting in different levels of drug resistance. Drug target alteration is one of the most common mutational devices, diminishing the degree to which medications attach to proteins within the blood, and thus limiting the resistance. Abrogation of prodrug activation, another subtype, results in the insusceptibility to some of first-line (isoniazid and pyrazinamide) and second‑line drugs (ethionamide and para-aminosalicylic acid, for instance). In this way, the abundance of how M. tuberculosis may adapt to gain better longevity renders TB as dangerous as it is nowadays.

Several factors of the relatively fast evolution of M. tuberculosis’s well-adapted strains may be attributed to the human element. Incompetent application of control measures, interrupted drug supply, drugs of low quality, and patient non-adherence may all contribute to the process, although their influence is not sufficient to explain it thoroughly. The evolution of drug resistance and treatment failure may be the result of the actual doses used, which seemingly are insufficient to produce an amount of a drug able to sterilize. The variable degree of drug perforation into TB lesions is another contributing factor. The prescription of standard second-line drugs in the presence of primary drug resistance, followed by their replacement, as well as intermittent courses of therapy, leads to the accumulation of mutations, which become the main reason for the development of the drug resistance. In this way, it is partially formed as a result of one or more spontaneous mutations in M. tuberculosis genes, which occur predominantly when inadequate medication regimens are used.

Moreover, bacteria fitness is potentially another critical element to understanding the evolution of antimicrobial drug resistance in M. tuberculosis. The growth of the insusceptibility to medication in a bacterial population is related to the rate of drug-resistant mutations, the acquisition of horizontally transmitted genes, and fitness cost in bacteria (Zhan et al., 2020). Bacteria fitness, which may be defined as an ability to replicate, survive and undergo transmission, in the specific case of M. tuberculosis, is enhanced in the presence of antimicrobial medication (Zhan et al., 2020). The rate of replication may be reduced when the drug is absent, and the mechanics of the process necessitate further investigation.

The de novo evolution of drug resistance, a series of genetic mutations present for the first time, is influenced by several factors, among which the most significant are the population size, the mutation rate, and the mutational target size. Determining the individual contribution of each of the elements to the scale of resistance acquisition is a complex process, as the net of relations between them is not clear. The size of the bacterial population correlates with the number of cell division events, which increases the chances of drug resistance evolution. Additionally, the earlier these mutations occur in the history of the population, the more substantial part of it will be resistant to the medication in question. The higher cell density increases the chances of encountering drug-resistant M. tuberculosis variants. Nevertheless, measuring the number of bacterial cells in the lungs of a patient is not a trivial procedure. The mutation rate may be described as the frequency with which new mutations occur, and determining its rate for M. tuberculosis may seem improbable because of its long generation time.

Genetic background is a factor that influences the process in question and is the center of heated discussions. The link between the ability to resist the impact of a drug and the diminishing fitness of M. tuberculosis bacteria when the antibiotics are absent is well-established. Isoniazid unsusceptible M. tuberculosis variants were used in studies to support the concept experimentally. Furthermore, drug resistance may be measured by the mutation rate that occurs and its target size. The scale of drug resistance is usually calculated using Luria-Delbruck fluctuation; nevertheless, performing the fluctuations is a laborious task, and the extent to which it is applied is limited. Taking this into consideration, the usual recommendations of medicating TB with a combination of drugs are rooted in its structural specifics.

Four drug-combination may be considered as a possible option for treating TB when the disease is caused by susceptible to medication M. tuberculosis strains. The mechanisms of the approach are grounded in the low probability for a strain to undergo four mutations that would render it resistant to the four medications. However, if the M. tuberculosis strains already possess a certain degree of resistance to one of the drugs, the chances of becoming fully drug‑unsusceptible are higher. Thus, similar mutations can occur in the mycobacterial population even before contact with the anti-TB drugs.

The significance of investigating antimicrobial resistance in M. tuberculosis stems first of all from the need to contain the disease, which is complicated by the steadily increasing number of TB strains that are unsusceptible to treatment. The issue is further emphasized by the low number of compounds aimed specifically at TB. The results of the article in question for the rapid development of molecular genetics observed in recent years have opened up opportunities for studying the M. tuberculosis genes that control drug resistance and the mechanisms of its evolution. The most studied genes and mechanisms of drug-resistance formation are for first-line drugs, as shown in the article, and the same issues for second-line medications are to be investigated further. The problem of increasing the effectiveness of measures to prevent the infection with drug‑resistant M. tuberculosis strains is another topic of interest for research that may be based on the text.

References

Fong, I.W., Shlaes, D., & Drlica, K. (2018). Antimicrobial Resistance in the 21st Century. Springer.

Gengenbacher, M., & Kaufmann, S. H. E. (2012). Mycobacterium tuberculosis: Success through dormancy. FEMS Microbiology Reviews, 36(3), 514–532.

Gygli, S. M., Borrell, S., Trauner, A., & Gagneux, S. (2017). Antimicrobial resistance in Mycobacterium tuberculosis: Mechanistic and evolutionary perspectives. FEMS Microbiology Reviews, 41(3), 354–373.

Maitra, A., Munshi, T., Healy, J., Martin, L. T., Vollmer, W., Keep, N. H., & Bhakta, S. (2019). Cell wall peptidoglycan in Mycobacterium tuberculosis: An Achilles’ heel for the TB-causing pathogen. FEMS Microbiology Reviews, 43(5), 548–575.

Zhan, L., Wang, J., Wang, L., & Qin, C. (2020). The correlation of drug resistance and virulence in Mycobacterium tuberculosis. Biosafety and Health, 1–7.

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