Antibiotic Resistance: Cause and Mechanism

Scope of antibiotic resistance problem:

Antibacterial-resistant strains and species, occasionally referred as “superbugs”, now contribute to the emergence of diseases that were well controlled few decades ago. In a recent report “Antibiotic Resistance Threats in the United States, 2013,” CDC calls this as a critical health threat for the country. According to the report more than 2 million people in the United States get antibiotic resistant infections each year and at least 23,000 of them die annually. Now, this is the situation in a country where drug regulations are quite tough and stringent and physicians are relatively careful in prescribing medications. Imagine the situation in developing countries like India, where antibiotics are available over the counter without medical prescription and more than 80-90% of population use antibiotics without physician’s consultation. In fact they are not even aware of the proper use of the antibiotic course. This is again a huge health challenge that will pose even more serious threat in coming years in treating antibiotic resistant infections. Recently, in a clinic in Mumbai some 160 of the 566 patients tested positive for TB between March and September that were resistant to the most powerful TB medicine. In fact, more than one-quarter of people diagnosed with tuberculosis have a strain that doesn’t respond to the main treatment against the disease. According to WHO and data from Indian government, India has about 100,000 of the 650,000 people in the world with multi-drug-resistance.

 Factors contributing to antibiotic resistance:

Inappropriate treatment and misuse of antibiotics has contributed maximum to the emergence of antibacterial-resistant bacteria.Many antibiotics are frequently prescribed to treat diseases that do not respond to these antibacterial therapies or are likely to resolve without any treatment. Most of the time incorrect or suboptimal doses of antibiotics are prescribed for bacterial infections. Self-prescription of antibiotics is another example of misuse. The most common forms of antibiotic misuse however, include excessive use of prophylactic antibiotics by travelers and also the failure of medical professionals to prescribe the correct dosage of antibiotics based on the patient’s weight and history of prior use. Other misuse comprise of failure to complete the entire prescribed course of the antibiotics, incorrect dosage or failure to rest for sufficient recovery. Other major causes that contribute to antibiotic resistance are excessive use of antibiotics in animal husbandry and food industry and frequent hospitalization for small medical issues where most resistant strains gets a chance to circulated among the community.

To conclude, humans contribute the most to the development and spread of drug resistance by: 1) not using the right drug for a particular infection; 2) not completing the antibiotic duration or 3) using antibiotics when they are not needed.

In addition to the growing threat of antibiotic-resistant bugs, there may be another valid reason doctors should desist from freely prescribing antibiotics. According to a recent paper published online in Science Translational Medicine, certain antibiotics cause mammalian mitochondria to fail, which in turn leads to tissue damage.

 Mechanism of antibiotic resistance:

Antibiotic resistance is a condition where bacteria develop insensitivity to the drugs (antibiotics) that generally cause growth inhibition or cell death at a given concentration.

Resistance can be categorized as:

a) Intrinsic or natural resistance:  Naturally occurring antibiotic resistance is very common, where a bacteria may be simply, inherently resistant to antibiotics. For example, Streptomyces possess genes responsible for conferring resistance to its own antibiotic, or bacteria naturally lack the target sites for the drugs or they naturally have low permeability or lack the efflux pumps or transport system for antibiotics. The genes which confer this resistance are known as the environmental resistome and these genes can be transferred from non-disease-causing bacteria to the disease causing bacter, leading to clinically significant antibiotic resistance.

b) Acquired resistance: Here a naturally susceptible microorganism acquires ways not to get affected by the drug. Bacteria can develop resistance to antibiotics due to mutations in chromosomal genes or mobile genetic elements e.g., plasmids, transposons carrying antibiotic resistance genes.

The two major mechanisms of how antibiotic resistance is acquired are:

Genetic resistance: It occurs via chromosomal mutations or acquisition of antibiotic resistance genes on plasmids or transposons.

Phenotypic resistance: Phenotypic resistance can be acquired without any genetic alteration. Mostly it is achieved due to changes in the bacterial physiological state. Bacteria can become non-susceptible to antibiotics when not growing such as in stationary phase, biofilms, persisters and in the dormant state. Example: Salicylate-induced resistance in E. coli, Staphylococci and M. tuberculosis.

In genetic resistance category, following are the five major mechanisms of antibiotic drug resistance, which occurs due to chromosomal mutations:

1. Reduced permeability or uptake (e.g. outer membrane porin mutation in Neisseria gonorrhoeae)

2. Enhanced efflux (membrane bound protein helps in extrusion of antibiotics out of bacterial cell; Efflux of drug in Streptococcus pyogenes, Streptococcus pneumoniae)

3. Enzymatic inactivation (beta-lactamases cleave beta-lactam antibiotics and cause resistance)

4. Alteration or over expression of the drug target (resistance to rifampin and vancomycin)

5. Loss of enzymes involved in drug activation (as in isoniazid resistance-KatG, pyrazinamide resistance-PncA)

Examples of transfer of resistance genes through plasmid are; Sulfa drug resistance and Streptomycin resistance genes, strA and strB while the transfer of resistance gene through transposon occurs via conjugative transposons in Salmonella and Vibro cholera.

In the next post, I will discuss few important examples of antibiotic resistance in clinically relevant microbes.

Antibiotics: Wonder drugs or a threat to public health?

What are antibiotics?

Antibiotics, also known as antibacterials, are category of medications which kills or slow down the bacterial growth. Penicillin was the first antibiotic, discovered by Sir Alexander Fleming in 1928, but it was not until the early 1940s that its true potential was recognized before it came into widespread use. In 1942, the term antibiotic was first used by Selman Waksman. In earlier days, antibiotics were often referred as “wonder drugs” because they cured several bacterial diseases that were once fatal. With antibiotic use, the number of deaths caused by bacterial infections like meningitis, pneumonia, tuberculosis, and scarlet fever were drastically reduced.  Discovery of antibiotics have revolutionized human development in a highly significant way. Other than vaccines, few medical discoveries had such a huge impact on healthcare delivery. Major complicated surgeries, transplants, advances in neonatal medicine, and advances in chemotherapy for cancer patients would not be possible without antibiotics.

Antibiotics classification:

Antibiotics are broadly classified based on their mechanism of action, structure, source or origin of the antibacterial agent or their biological activity. With the recent advances in medicinal chemistry, most antibiotics available nowadays are semisynthetic derivative of various natural compounds (penicillins, Cephalosporins and Ampicillin). Very few antibiotics like aminoglycosides (Streptomycin, Gentamicin, and Neomycin) are isolated from living organisms while many other antibiotics, Sulfonamides,Quinolones, Moxifloxacin and Norfloxacin are chemically synthesized. Based on the biological activity of the microorganisms, antibiotics are classified as bactericidal agents (which kill bacteria) and bacteriostatic agents (which slow down or impede bacterial growth). Microorganisms are known to develop resistance faster to the natural antimicrobials since they have been pre-exposed to these compounds in nature. Therefore semisynthetic drugs were developed for increased efficacy and less toxicity. Synthetic drugs possess an added advantage that bacteria are not exposed to these compounds until they are released systemically. They are designed to have even improved effectiveness with decreased toxicity.

Antibiotics are also classified based upon their range of effectiveness. Broad-spectrum drugs are effective against many types of microbes (gram-positive and gram-negative) and tend to have higher toxicity to the host. Narrow-spectrum drugs are effective against a limited group of microbes (either gram-positive or gram-negative) and exhibit lower toxicity to the host. Based on the chemical structure, antibiotics are classified into two categories: β-lactams and aminoglycosides. All the above mentioned classes of antibiotics are further divided according to their targets or mode of action in the bacteria. Following are the five important antibiotic targets in bacteria.

1. Inhibitors of cell wall synthesis (-cillins)

2. Inhibitors of protein synthesis (-mycins)

3. Inhibitors of membrane function (Polymyxin)

4. Anti-metabolites (Sulfa drugs)

5. Inhibitors of nucleic acid synthesis (Nalidixic acid, Rifampicin)

 The deluge of antibiotic resistance bacteria:

“The first rule of antibiotics is try not to use them, and the second rule is try not to use too many of them”, a quote by Paul L. Marino. Well, after an era of plentiful antibiotics, presently, the situation is alarming due to the ever increasing number of antibiotic resistant strains. In early years, new antibiotics were developed faster than bacteria developed resistance to them. But the bugs have caught up fast now. In the 1950s and 60s, many new classes of antibiotics were discovered. However, in 1980s and 1990s, scientists have only managed to make improvements within different classes of antibiotics.

 The emerging resistance of bacteria to antibacterial drugs is becoming a continuous threat to human health. Bacterial resistance to penicillin was observed within 2 years of its introduction in mid 1940s. Rapidly emerging resistance to ciprofloxacin and various anti-tuberculosis drugs indicates that it is microbe’s world and they are ready to adapt. Since, microbes congregate in large numbers to induce infection, generate rapidly and mutate efficiently, developing resistance is not a matter of “if” but of ‘when”. To overcome any assault, bacteria possess efficient defense system present within DNA or chromosomes or extrachromosomal elements called plasmid. The bacteria have advantage that these plasmids carrying resistance gene with them can easily shuttle between bacterial cells and humans.

Now, no longer limited to the hospitals, antibiotic resistance with Neisseria gonorrhea and Streptococcus pneumoniae is becoming a household and a community setting phenomenon. The use of surface antibacterials in common households, self-medication and unregulated sales of antibiotic in many countries are further aggravating the problem. According to a CDC report by the end of 20th century, approximately 30 % of S. pneumoniae (causative agent of meningitis, otitis media and pneumonia) were no longer found to be sensitive against penicillin. Similarly, treatment failures were observed in patients because of the resistant strains of, Shigella, Salmonella typhi, Staphylococcus, Mycobacteria tuberculosis, Klebsiella pneumoniae, Clostridium difficle and S. pneumoniae. Drug-resistant bacteria can be acquired in community settings like, daycares, schools and other crowded places. Other risk factors are antibiotic use and consumption of food products treated with antibiotics. Increased use of quinolones in poultry and farm animals has been associated with the increased prevalence of human infection with quinolone-resistant Salmonella and Campylobacter.  Besides, the established pathogens, relatively recent appearance of opportunistic organisms, intrinsically resistant to many drugs are making the matter worse. With a larger number of immunocompromised patients, these organisms have become ‘specialized’ pathogens—typically attacking only the most vulnerable patients. Examples of such opportunistic pathogens are Enterococci, the coagulase-negative Staphylococci, Pseudomonas aeruginosa and Acinetobacter baumanii. Therefore, it is the high time to think and act to reverse this trend of antibiotic resistance by medical professionals by creating awareness among communities on the proper use of antibiotics and discouraging self-medications. In the next series, I will discuss the factors responsible for antibiotic resistance and its detailed mechanism.

 

Academic Journals

Academic journals are also known as periodicals. They usually include the research works of a variety of people specialising in diverse areas of academics. Academic journals are not written by every regular author, but only by professionals who are approved to share their opinions, knowledge and researches with a huge community consisting of educationists, professors and students. The reason behind writing in academic journals is to enhance the information in universal and in explicit sense, as well as to share the information with students and other experts belonging to the same field or discipline.

The present article on “Academic Journals” gives detailed information about academic journals and some basic tips as guidance while writing for academic journals.

Types of Academic Journals

Academic journal writing differs on the basis of its subject matter. In a broader sense, academic journals can be characterised under the following types.

  • Art journals
  • Arts and Education
  • Biological Sciences
  • Business Journals
  • Legal Studies
  • Medical Sciences
  • Physical Sciences
  • Research Journals
  • Scholarly Journals
  • Science Journals
  • Social Sciences

Tips for Academic Journals Writing

In order to produce a remarkable piece of content, which is suitable for publishing, it is necessary to follow specific kinds of formats and procedures.

  • Ensure to write significant and relevant points and sentences. Avoid unnecessary and repetitive information. Pay extra attention while selecting words and phrases.
  • Try to maintain a formal tone in your writing. Besides, ensure that the sentences are composed from the viewpoint of a third party.
  • Remember that the readers of your articles are people from your own field or discipline. Thus, it is typical to assume that they already possess basic knowledge about what you will be writing. Consequently, this eliminates the need of explaining the information in much detail.
  • Ensure to format and organise your written matter into various segments so that the article looks well-arranged and easy to comprehend.
  • Although not mandatory, it is always beneficial to go through the process of peer review. By the help of this process, one or more professionals belonging to your specific field will read and analyse your written material and provide suggestions for improvement.
  • After finishing writing the article, ensure to revise and proofread it. Read it again and again to check and eliminate any kind of mistake in spellings, punctuation, grammar, concepts, and/or reasoning.

Writing for academic journals is not that tough if taken proper steps and assistance. As these journals are usually written by professionals, there are fewer chances of errors, but one can never be too sure about this. Hence, it is advised to follow some basic tips and guidelines while writing your articles for academic journals in order to avoid any kind of mistake or error.