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.

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