By Barry C. Fox, M.D., University of Wisconsin
In a national report, it was estimated that bacteria resistant to all antibiotics resulted in 23,000 deaths and two million illnesses a year in the United States alone. Read on to learn about eight different classes of antibiotics and different methods of bacterial resistance.
The Famous Lifesavers and How They Work
Penicillin is the antibiotic group known as the beta lactams, named after their structure. Beta lactams bind to proteins on the bacterial cell wall surface and then interfere with a bacterial enzyme that is involved in the cross-linkages among the outer layer of the bacterial cell wall.
Sulfonamides are another class of antibiotics, which work by disrupting the pathway that leads to the synthesis of DNA. Folic acid is a building block needed for DNA synthesis, and it structurally resembles sulfonamides.
The two compounds compete to acquire an enzyme known as para-aminobenzoic acid, which is necessary for folate production, and subsequently for DNA synthesis. Derivatives of the sulfonamide drugs over the next few decades formed one of the key foundations for antimicrobial therapy, and continue to be used today.
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An Upgrade from Penicillin Is Due
Streptomycin was the first drug useful for tuberculosis, or TB, treatment. Not only was streptomycin able to treat TB, but it was also useful in curing Gram-negative bacterial infections, which penicillin could not.
However, when streptomycin was used alone for TB, not unexpectedly, resistance emerged, and damage by streptomycin to the kidneys prompted further development of an improved antibiotic, neomycin.
Both of these drugs belong to the class of antibiotics known as aminoglycosides. More advanced aminoglycoside derivatives are still in use today.
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The Broad-spectrum Antibiotics
Chloramphenicol was the first ‘broad-spectrum’ antibiotic to exhibit activity against germs with different cell walls and different gram staining characteristics.
In 1948, another broad-spectrum antibiotic named aureomycin was being studied. This was a prototype drug for the class of drugs known as tetracycline.
With their broad spectrum of activity and rare side effects, tetracycline emerged as a major class of antibiotic that is still used today, second only to beta lactam penicillins. Erythromycin is another antibiotic class in use for nearly 50 years.
In the 1970s, trimethoprim was introduced as a synthetic antimicrobial. A novel idea occurred to chemists that if they combined two antibiotics at different steps in the same crucial folate metabolic pathway, the combined drugs would be more effective at interrupting DNA synthesis.
This resulted in trimethoprim-sulfamethoxazole, which is still one of the first-line antibiotics utilized for the treatment of bladder infections, and is also effective for MRSA.
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The Unique Drugs that Killed Everything
The final class of antibiotics for discussion are also synthetic drugs derived from a compound known as nalidixic acid. This prototype was used for the development of a broad-spectrum class of drugs known as the quinolone antibiotics, introduced in the 1980s.
Due to widespread use as a broad-spectrum ‘kill everything’ antibiotic, not surprisingly, resistance has emerged to the quinolone class. Unfortunately, quinolones are also exploited for food and growth promotion in livestock animals, also leading to resistance that has at times been transferred to humans.
How Bacteria Develop Resistance against Antibiotics
In the example of someone who is in the hospital with a severe leg infection and is allergic to penicillin—in this case, penicillin can’t be used to fight the infection.
A culture has shown MRSA, so cephalosporins are out as well. MRSA from the hospital is usually resistant to tetracyclines, sulfonamides, and quinolones.
What’s left? Well, fortunately, there are a few antibiotics left, but the treatment dilemma can be seen.
The Resistance Paradox in Treating Bacterial Diseases
For every mechanism of action of an antibiotic, it is virtually assured that there is a mechanism of resistance. When bacteria divide they duplicate their DNA, proteins, and cell walls. According to Nobel Laureate Joshua Lederberg, who discovered the bacterial exchange of DNA among bacteria: “It’s a race between their genes and our wits.”
They also replicate at a rapid rate, and each time there’s a division of cells, there’s a chance for genetic mutations for any of these three cell products to occur.
The genetic mutation can occur at the level of the genes or within the chromosomes, or in extra-chromosomal genes that exist in the cytoplasm, known as plasmids.
There are ample opportunities for bacteria to share genetic material, including many genes that can encode for resistance. The mechanisms of bacterial resistance can be divided into four different general categories: enzyme inactivation, altered bacterial membrane target site, altered other target sites (such as a ribosome), and antibiotic efflux pumps.
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The Resistance Tactics the Enemy Uses
First, the basic mechanism of resistance to Alexander Fleming’s penicillin is an example of enzyme inactivation. Resistant bacteria produce an enzyme that results in the disruption of the penicillin ring, hence rendering penicillin unable to structurally block cell wall synthesis.
The example of hospitalization for a leg infection can be used to describe the second mechanism. Due to alterations of the structure of the cell-membrane penicillin-binding protein target sites, the Staphylococcus is now resistant to methicillin and cephalosporins, and hence it’s called MRSA.
As an illustration of the third mechanism, Streptococcus Pneumonia also can become resistant to antibiotics that act on the ribosomal protein-synthesis target site. If a methyl chemistry group is added to the ribosome, antibiotics working at this site such as erythromycin may be unable to bind to the ribosome.
Fourth and finally, increasing the bacteria’s capacity to actively pump antibiotics out of the cell before they’re able to exert their antibiotic effect is seen with a wide assortment of bacteria.
To make matters worse, some bacteria possess multiple mechanisms of resistance simultaneously, resulting in resistance to several different classes of antibiotics, such as with a leg infection with MRSA. This leads to bacteria known as multiple drug-resistant or extensively drug-resistant.
Common Questions about How Different Groups of Antibiotics Fight Bacteria and How Bacteria Fight Back
An enzyme that is involved in the structure of bacterial cell wall stops working when it encounters a group of antibiotics called beta lactems, because of their tendency to stick to proteins on the cell wall.
The first drug that was proved to be effective against tuberculosis bacteria was Streptomycin.
Because it is a broad-spectrum antibiotic, meaning it kills both Gram-positive and Gram-negative bacteria, it has been overused by doctors. Worse than that is that it’s used in animals that we eat so resistance against it is growing even more.
