Quinolone Antibiotics: Medicine at its Best

by Rachel Boutom, Sneha Kabaria, and Andrea  Thomas

Antibiotics have been essential to mankind since the discovery of penicillin, and have since branched out into many classes and thousands of medications. This article will explore the class of antibiotics referred to as “quinolone antibiotics” due to its quinolone nucleus. The quinolone nucleus contains double-ring structure composed of benzene and pyridine rings fused at two adjacent carbon atoms. The benzene ring contains six carbon atoms, while the pyridine ring contains five carbon atoms and a nitrogen atom. There are many variations, four generations, different functions, benefits, and side effects to quinolone antibiotics, and you will learn all about them here.

What is Quinolone?

Quinolone is an antibiotic that works by interfering with DNA replication and bacterial transcription.

http://www.youtube.com/watch?v=3IFSxbEvY7g.

The quinolone carries out this function by inhibiting bacterial DNA Gyrase, which is responsible for the negative supercoiling of the DNA, and bacterial Topoisomerase IV, which is an enzyme needed for the separation of strands after replication during cell division. It was first discovered in 1962 as nalidixic acid, which is considered to be the first drug in the quinolone family. From then, there have been four generations of drugs based on their antibacterial spectrum. There is no set standard of classification system to base the drugs on, however there are general properties that differ.

The earlier-generation agents have, in general, more narrow-spectrums than the later ones. In addition, all non-fluorinated drugs in the quinolone class are labeled as first-generation antibiotics. The majority of quinolone antibiotics used today are fluorinated, meaning they have a fluorine atom bonded to the six-carbon ring. These are called fluoroquinolones. Fluoroquinolones are broad-spectrum antibiotics which are effective for both gram negative and gram positive bacteria, and they play an important role in treatment of serious bacterial infections, especially hospital-acquired infections and others in which resistance to older antibacterial classes is suspected.

 

How is it Synthesized?

All quinolines are synthetic, meaning they do not occur in nature, and thus, must all be synthesized in laboratories. Since the creation of the first quinoline nalidixic acid, over 10,000 analogues and derivative compounds have been developed, and more than 800 million patients have been treated with quinolones. There are many ways of synthesizing this chemical: the Gould-Jacob’s method using esters, hydrolysis, and regiospecific substitution; the Modified Gould-Jacobs method, using Isatoic Anhydride and Sodio-Ethyl Formyl Acetate; and many more.

Pharmacokinetics

The newer fluoroquinolone antibiotics also have improved pharmacokinetic parameters compared with the original quinolones. They are rapidly and almost completely absorbed from the gastrointestinal tract. Peak serum concentrations obtained after oral administration are very near those achieved with intravenous administration. Consequently, the oral route is generally preferred in most situations Absorption of orally administered fluoroquinolones is significantly decreased when these agents are coadministered with aluminum, magnesium, calcium, iron or zinc, because of the formation of insoluble drug.

Because the fluoroquinolones have a large volume of distribution, they concentrate in tissues at levels that often exceed serum drug concentrations. Penetration is particularly high in renal, lung, prostate, bronchial, nasal, gall bladder, bile and genital tract tissues. Urine drug concentrations of some fluoroquinolones, such as ciprofloxacin and ofloxacin (Floxin), may be as much as 25 times higher than serum drug concentrations. Consequently, these agents are especially useful in treating urinary tract infections.

Distribution of the fluoroquinolones into respiratory tract tissues and fluids is of particular interest because of the activity of these agents against common respiratory pathogens. Trovafloxacin penetrates noninflamed meninges and may have a future role in the treatment of bacterial meningitis. The long half-lives of the newer fluoroquinolones allow once- or twice-daily dosing.

Bacterial Resistance

As with all antibiotic medicines, the potential for the development of antibacterial resistant strains of bacteria is always a threat. This has already been found to be a problem with quinolones. Gram-positive and gram-negative bacteria have been reported to be resistant to quinolones, and there are different mutations that cause this. The resistance appears to be the result of one of three mechanisms: alterations in the quinolone enzymatic targets (DNA gyrase), decreased outer membrane permeability or the development of efflux mechanisms. In addition, cross-resistance between quinolones is to be expected in the future.

One of the largest problems with antibacterial resistance is the degree to which the same medication is used, which leads to the problem of the extent to which the resistant strain is spread and recreated in other places. For a long period of time, the increased potency and effectiveness of the newer generation of fluoroquinolones, as compared to the older quinolones, led to an unregulated increase in their use. As they kept working effectively, their use proportionally increased, with a 40% increase in use in the United States during the 1990s. During this period, the rate of resistance to the two pain fluoroquinolones doubled, specifically in areas such as the intensive care units in hospitals.

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What Might Life On Europa Be Like?

Image From A Fictional Movie, Not Intended to Be Realistic

Hydrothermal Vents

 

Before speculating about what kinds of life could conceivably live on Europa, we should first talk about where it’s most likely going to be. At first, you might think that because life on Europa couldn’t possibly have access to adequate sunlight, there isn’t going to be any source of food for any potential lifeforms. However if you’ve been reading our blog posts from the beginning, you’ll know that Europa possibly has an underground liquid water ocean that stays liquid due to heat from its tidal interactions between Jupiter and the other moons. Because of this Europa likely has Plate Tectonics just like Earth. At the plate boundaries, magma can get exposed to the water creating incredibly hot hydrothermal vents.

On Earth

 

When hydrothermal vents are on land, they become better known as hot springs and geysers. However, we are more interested in the vents at the bottom of the ocean. The conditions around those vents more closely approximate the conditions that any life on Europa would have to endure than anywhere else on Earth. Despite the extreme pressures, heat, and complete lack of sunlight, biodiversity flourishes in these environments.

Bottom of the Food Chain

Despite having next to no energy from the sun, bacterial life surrounding hydrothermal vents flourishes. These organisms get their energy from Chemosynthesis rather than photosynthesis. Chemosynthesis is the creation of energy rich organic compounds using energy from non-organic chemicals rather than light. Chemosynthesis cannot one set of chemical equations like photosynthesis because there are many different types of it.

One of the very important forms of chemosynthesis here on Earth is Hydrogen Sulfide Chemosynthesis. This form of energy production is the source of most of the energy feeding the communities surrounding Earth’s hydrothermal vents.  Microscopic organisms like the Purple Sulfur Bacteria are capable of oxidizing the sulfur in hydrogen sulfide to elemental sulfur and forming glucose as described in the chemical equation below. This yellow elemental sulfur can actually be seen in cytoplasm of the bacteria

12H2S + 6CO2 → C6H12O6 + 6H2O + 12S

Methanogenesis on the other hand involves the reduction of the carbon in CO2 to methane and the oxidation of some of the hydrogen in hydrogen gas to water. Unlike hydrogen sulfide chemosynthesis, Methanogenesis is very common in less extreme environments. Bacteria that undergo methanogenesis are found everywhere from plants to the human digestive system. It is also considered by many scientists to be a very possible source of energy for life on Europa and might be able to explain the amount of methane in Europa’s atmosphere.

CO2 + 4 H2 → CH4 + 2 H2O

Infrared Photosynthesis

Another completely different way to produce energy at the bottom of the ocean actually relies on the same principles that life elsewhere does. As everyone knows, if you heat a metal enough, it will begin to emit red light. It turns out that it actually was emitting light the entire time just not in the visible spectrum. As the metal got hotter and more energetic, the energy of the light it emitted became higher in frequency, lower in wavelength, and more energetic.This phenomenon, known as blackbody radiation, occurs in all matter at all temperatures including heated water near hydrothermal vents. This water is still not hot enough to emit visible light. However, some species of bacteria, like green sulfur bacteria have adapted a method of photosynthesis that works off of infrared wavelengths, light that has too large a wavelength to see.

Large Organisms

With the bacteria converting just about any energy they can get their hands on into food, larger organisms are able to feed off of them creating complex ecosystems surrounding these hydrothermal vents. The same could be true of Europa, meaning that any kind of microscopic life could lead to much more interesting alien ecosystems. For instance the Giant Tube Worm that inhabit many of the hydrothermal vents have a symbiotic relationship with chemosynthetic bacteria that live inside a specialized organ in the tube worm. The bacteria then provide nutrients to the tube worm that would otherwise not be present at the bottom of the sea. While most of the animals inhabiting these depths of invertebrates like the tube worm, a community of eel’s has even been found near American Samoa.