Introduction
Antimicrobial resistance is a major issue of public health because it affects the treatment of pathogenic microbes such as bacteria. Microbial organisms usually acquire resistance to chemicals that they encounter in their environment as a means of adapting and surviving. Antimicrobial resistance is a deliberate way of adaptation and evolution of bacteria through genetic and biochemical changes that enhance survival ability (1). As a pathogenic bacterium, Helicobacter pylori resides in the stomach and causes gastric ulcer among individuals. H. pylori, which is prevalent among 50-70% of the global population, has acquired resistance against antimicrobials(2). Therefore, the aim of the essay is to examine the problem of resistance in H. pylori and describes its mechanisms.
The Problem of Antimicrobial Resistance
Antimicrobial resistance is the major challenge that affects the eradication of H. pylori, the main causative bacterium of gastric ulcers. The World Health Organization has classified H. pylori as a group 1 carcinogen because it causes peptic ulcers, chronic gastritis, gastric cancer, and gastric lymphoma(2,3). The common drugs used in the eradication of H. pylori are tetracycline, furazolidone, levofloxacin, rifabutin, amoxicillin, metronidazole, and clarithromycin. However, the increasing development of resistance across the globe has challenged the use of these drugs for they are no longer effective. Specifically, resistance to clarithromycin has registered high rates, which are 50% in China, 40% in Turkey, and 30% in Japan(4). An extensive literature review reveals that resistance to amoxicillin, tetracycline, and metronidazole is higher in Africa, whereas resistance to levofloxacin an clarithromycin is higher in Asia and North America(5). In essence, resistance to certain antibiotics varies from one region to another.
Additionally, the resistance of H. pylori varies from one antibiotic to another. A comparative study of resistance rates reveals that metronidazole, clarithromycin, levofloxacin, amoxicillin, tetracycline, furazolidone, and rifabutin have 47.22%, 19.74%, 18.94%, 14.67%, 11.70%, 11.5%, and 6.75% respectively(5). In this view, it is apparent that metronidazole is the least effective antibiotic, while rifabutin is the most effective antibiotic. Antibiotic resistance in H. pylori emanates from constant use of antibiotics, particularly, clarithromycin in the treatment of respiratory, paediatric, and otorhinolaryngologic diseases. The rates of clarithromycin resistance have increased in Japan from 7% to 27.7% and in Europe from 9% to 17.6% during 2000-2006 and 1998-2008 respectively(3). Such trends present clarithromycin as an important indicator of H. pylori resistance in various regions across the globe.
The increasing occurrence of resistance to major antibiotics has led to the use of combined antibiotics to enhance effectiveness and avert the development of resistance. The triple or quadruple therapy comprising proton pump inhibitors, mucosa protective agent, and antibiotics has proved to be effective in the eradication of H. pylori(2). However, the use of triple therapy as recommended by the first Maastricht conference has not been effective due to the increasing resistance in H. pylori. Currently, the efficacy of the triple therapy has declined to about 70%, leading to the recommendation of the quadruple therapy(3). The fourth Maastricht conference recommends consideration of clarithromycin resistance in the use of antibiotics against H. pylori. Clarithromycin-based regimens are effective as first-line treatment in regions with low resistance, whereas the quadruple regimens with bismuth or levofloxacin are appropriate as first-line treatment in regions with low resistance(5). Thus, the analysis of resistance in H. pylori shows that the determination of the individual, local, and global rates of resistance is essential to allow customisation of treatment regimens. Moreover, the use of patient-specific antibiotics has the potential of reducing treatment failures and preventing the development of resistance.
Mechanisms of Resistance
H. pyloric has numerous mechanisms that it uses in gaining resistance to major antibiotics. Gong and Yuan outline that H. pylori resists antibiotics using genetic mutations, alteration of the cell membrane, expression of catabolic enzymes, secretion virulence factors, and adaptation(2). The mechanisms of resistance are dependent on molecular and cellular changes coupled with the pharmacodynamics and pharmacokinetics of antibiotics in the eradication of H. pylori.
Genetic Mutation
H. pylori undergoes genetic mutation in evolving and adapting to diverse environments and chemicals with a view to gain resistance to antibiotics. Since antibiotics target cellular and molecular processes to disrupt cell division, genetic replication, transcription, and translation, H. pylori mutates its genes to evade the effects of antibiotics. Target genes involved in the synthesis of enzymes, such as DNA gyrase, the DNA-dependent RNA polymerase, and redox enzyme (2,6). DNA gyrase is an enzyme that plays a critical role in maintaining the integrity of DNA and promoting replication and transcription of DNA gyrase. Inhibition of DNA gyrase by antibiotics causes irreversible damage to DNA, resulting in the eradication of H. pylori. Hence, mutations in two genes, namely, gyrA and gyrB, which encodes for DNA gyrase, gives quinolone resistance to H. pylori (6). Since some antibiotics target the activity of the DNA-dependent RNA polymerase, mutations in rpoB gene cause the occurrence of rifampicin resistance in H. pylori(2). Resistance occurs because rifampicin is unable to bind to the DNA-dependent RNA polymerase and block transcription of DNA into RNA.
Additionally, mutations that occur in genes encoding for redox enzyme (rdxA, frxA, and frxB) interfere with redox reactions, which are essential in enhancing the activity of antibiotics(2,7). Mutations that affect redox systems confer metronidazole resistance to H. pylori. Clarithromycin resistance ensues when mutations in V-domain of the 23S ribosomal subunit mutates and restores the ability H. pylori to translate proteins in presence of antibiotics. These mutations are single-nucleotide polymorphisms that cause changes functionality of transcription factors. Mutations in 16S ribosomal subunit cause tetracycline resistance by reducing affinity to the ribosome. Reduced affinity allows transcriptions and promotes replication of H. pylori(2,7). Since antibiotics target cell wall of H. pylori, mutations in genes that code for proteins involved in the synthesis of cell wall promotes resistance. The occurrence of mutations in pbp1A, a gene that encodes for penicillin-binding proteins causes H. pylori to acquire amoxicillin resistance(2). Thus, genetic mutations explain most of the mechanisms in H. pylori resistance to various antibiotics.
Alteration of Cell Membrane
Alteration of the cell membrane to hinder the entry and the accumulation o antibiotics in the bacterium is another mechanism of resistance. H. pylori has the outer membrane and transmembrane proteins that regulate the entry of molecules into it. Mutations in hopB and hopE, genes that encode for porins, and upregulation of their expressions reduces the permeability of cell membrane and causes amoxicillin resistance(2). At the outer surface of the cell membrane, H. pylori can form a biofilm, which protects the bacterium from antibiotics. H. pylori also uses efflux pump, AcrAB-TolC, with operons that excrete antibiotics and confer resistance to tetracycline, amoxicillin, metronidazole, and clarithromycin(2). A combination of biofilm and efflux pump is responsible for clarithromycin resistance.
Expression Enzymes and Virulence Factors
H. pylori expresses and secretes enzymes and factors that inactivate antibiotics or reduce their activity. H. pylori has the ability to express and secrete beta-lactamases, which break the beta-lactam ring and inactivates beta-lactam antibiotics, resulting in amoxicillin resistance(2). The use of amoxicillin with beta-lactamase inhibitors such as clavulanic acid increases the sensitivity of H. pylori. Additionally, expression of virulence factors, DupA and OipA, cause resistance to clarithromycin and the quadruple therapy respectively(2). H. pylori that expresses DupA stimulates the secretion of gastric acid and gastrin in high levels that cause resistance. The expression of OipA reduces cure rate for the quadruple therapy.
Adaptive Mechanism
H. pylori can initiate adaptive ways of evading antibiotics in the stomach. When it experiences harsh conditions, such as the presence of antibiotics, H. pylori undergoes morphological changes to form coccoid, which is a dormant phase that rejuvenates when antibiotics levels go down(2). Another adaptive mechanism is that H. pylori enters into microphages and epithelial cells to protect itself from eradication by antibiotics, although it is an extracellular pathogen. H. pylori induces autophagy to protect itself and replicate in host cells, resulting in resistance to antibiotics(2). Moreover, myriad of factors related to pharmacodynamics and pharmacokinetics of drugs contributes to the resistance of H. pylori to antibiotics.
Conclusion
As the causative agent of gastric ulcers, chronic gastritis, gastric cancer, and gastric lymphoma, H. pylori is a serious public health issue. The analysis of resistance shows that H. pylori has acquired resistance to metronidazole, clarithromycin, levofloxacin, amoxicillin, tetracycline, furazolidone, and rifabutin. The understanding of the mechanisms of resistance in H. pylori is integral in designing and developing effective antimicrobials required in the control and prevention of its occurrence in the population. Notable mechanisms of resistance are genetic mutations, modification of cell membrane, enzyme expression, secretion virulence factors, and adaptive features.
References
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