Wikipedia

Tetracycline antibiotics

This article is about the group of antibiotics known as the tetracyclines. For the specific antibiotic called "tetracycline", seetetracycline.

Tetracyclinesare a group ofbroad-spectrumantibioticcompounds that have a common basic structure and are either isolated directly from several species ofStreptomycesbacteriaor produced semi-synthetically from those isolated compounds.[1]Tetracycline molecules comprise a linear fused tetracyclic nucleus (rings designated A, B, C and D) to which a variety offunctional groupsare attached.[2]Tetracyclines are named after their four ( "tetra-" ) hydrocarbon rings ( "-cycl-" ) derivation ( "-ine" ). They are defined as a subclass ofpolyketides,having an octahydrotetracene-2-carboxamide skeleton and are known asderivativesof polycyclic naphthacene carboxamide.[3] While all tetracyclines have a common structure, they differ from each other by the presence ofchloro,methyl,andhydroxylgroups. Thesemodificationsdo not change their broad antibacterial activity, but do affectpharmacologicalproperties such ashalf-lifeand binding toproteinsinserum.[1]

Skeletal formula oftetracyclinewith atoms and four rings numbered and labeled.

Tetracyclines were discovered in the 1940s and exhibited activity against a wide range ofmicroorganismsincludinggram-positiveandgram-negative bacteria,chlamydiota,mycoplasmatota,rickettsiae,and protozoanparasites.[2]Tetracycline itself was discovered later thanchlortetracyclineandoxytetracyclinebut is still considered as the parent compound for nomenclature purposes.[4] Tetracyclines are among the cheapest classes of antibiotics available and have been used extensively in prophylaxis and in treatment of human and animal infections, as well as at subtherapeutic levels in animal feed as growth promoters.[2]

Tetracyclines are growth inhibitors (bacteriostatic) rather than killers of the infectious agent (bacteriocidal) and are only effective against multiplying microorganisms.[1]They are short-acting and passively diffuse throughporin channelsin the bacterial membrane. They inhibitprotein synthesisby binding reversibly to the bacterial30S ribosomal subunitand preventing theaminoacyl tRNAfrom binding to the A site of the ribosome. They also bind to some extent the bacterial50S ribosomal subunitand may alter thecytoplasmic membranecausingintracellularcomponents to leak from bacterial cells.

Tetracyclines all have the same antibacterial spectrum, although there are differences in species' sensitivity to types of tetracyclines. Tetracyclines inhibit protein synthesis in both bacterial and human cells. Bacteria have a system that allows tetracyclines to be transported into the cell, whereas human cells do not. Human cells therefore are spared the effects of tetracycline on protein synthesis.[1]

Tetracyclines retain an important role inmedicine,although their usefulness has been reduced with the onset ofantibiotic resistance.[2]Tetracyclines remain the treatment of choice for some specific indications.[2] Because not all of the tetracycline administered orally isabsorbedfrom thegastrointestinal tract,the bacterial population of theintestinecan become resistant to tetracyclines, resulting in overgrowth of resistant organisms. The widespread use of tetracyclines is thought to have contributed to an increase in the number of tetracycline-resistant organisms, in turn rendering certain infections more resilient to treatment.[1] Tetracycline resistance is often due to theacquisitionof new genes, which code forenergy-dependent effluxof tetracyclines or for a protein that protects bacterial ribosomes from the action of tetracyclines. Furthermore, a limited number of bacteria acquire resistance to tetracyclines by mutations.[2][5]

Medical uses

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Tetracyclines are generally used in the treatment of infections of the urinary tract, respiratory tract, and the intestines and are also used in the treatment ofchlamydia,especially in patients allergic toβ-lactamsandmacrolides;however, their use for these indications is less popular than it once was due to widespread development ofresistancein the causative organisms.[6][7] Tetracyclines are widely used in the treatment of moderately severeacneandrosacea(tetracycline,oxytetracycline,doxycyclineorminocycline).[8] Anaerobic bacteria are not as susceptible to tetracyclines as are aerobic bacteria.[9] Doxycyclineis also used as aprophylactictreatment for infection byBacillus anthracis(anthrax) and is effective againstYersinia pestis,the infectious agent ofbubonic plague.It is also used formalariatreatment and prophylaxis, as well as treating elephantitisfilariasis.[10] Tetracyclines remain the treatment of choice for infections caused bychlamydia(trachoma,psittacosis,salpingitis,urethritisandL. venereuminfection),Rickettsia(typhus,Rocky Mountain spotted fever),brucellosisandspirochetal infections(Lyme disease/borreliosisandsyphilis).[2]They are also used inveterinary medicine.[2] They may have a role in reducing the duration and severity ofcholera,although drug-resistance is mounting[11]and their effect on overall mortality is questioned.[12]

Side effects

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Side-effects from tetracyclines are not common, but of particular note isphototoxicity.It increases the risk of sunburn under exposure to light from the sun or other sources. This may be of particular importance for those intending to take on vacations long-term doxycycline as a malaria prophylaxis. They may cause stomach or bowel upsets, and, on rare occasions, allergic reactions. Very rarely, severe headache and vision problems may be signs of dangeroussecondary intracranial hypertension,also known asidiopathic intracranial hypertension. Tetracyclines areteratogensdue to the likelihood of causingteeth discolourationin the fetus as they develop in infancy. For this same reason, tetracyclines are contraindicated for use inchildrenunder 8 years of age. Some adults also experience teeth discoloration (mild grey hue) after use. They are, however, safe to use in the first 18 weeks of pregnancy.[13][14] Some patients taking tetracyclines require medical supervision because they can causesteatosisandliver toxicity.[15][16][17]

Cautions

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Tetracyclines should be used with caution by those with liver impairment. Also, because the molecules are soluble in water it can worsenkidney failure(this is not true of the lipid-soluble agents doxycycline andminocycline). They may increase muscle weakness inmyasthenia gravisand exacerbatesystemic lupus erythematosus.Antacids containing aluminium and calcium reduce the absorption of all tetracyclines, and dairy products reduce absorption greatly for all butminocycline. The breakdown products of tetracyclines are toxic and can causeFanconi syndrome,a potentially fatal disease affecting proximal tubular function in the nephrons of the kidney. Prescriptions of these drugs should be discarded once expired because they can cause hepatotoxicity. It was once believed that tetracycline antibiotics impair the effectiveness of many types ofhormonal contraception.Recent research has shown no significant loss of effectiveness in oral contraceptives while using most tetracyclines. Despite these studies, many physicians still recommend the use of barrier contraception for people taking any tetracyclines to prevent unwanted pregnancy.[18][19][20] In tetracycline preparation, stability must be considered in order to avoid formation of toxic epi-anhydrotetracyclines.[citation needed]

Contraindications

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Tetracycline use should be avoided in pregnant or lactating women, and in children with developing teeth because they may result in permanent staining (dark yellow-gray teeth with a darker horizontal band that goes across the top and bottom rows of teeth), and possibly affect the growth of teeth and bones. Usage during the first 12 weeks of pregnancy does not appear to increase the risk of any major birth defects.[21]There may be a small increased risk for minor birth defects such as aninguinal hernia,but the number of reports is too small to be sure if there actually is any risk.[21]

Mechanism of action

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Tetracycline antibiotics areprotein synthesis inhibitors.[22]They inhibit the initiation of translation in variety of ways by binding to the30S ribosomal subunit,which is made up of 16S rRNA and 21 proteins. They inhibit the binding ofaminoacyl-tRNAto themRNA translationcomplex. Some studies have shown that tetracyclines may bind to both 16S and 23S rRNAs.[23]Tetracyclines also have been found to inhibitmatrix metalloproteinases.This mechanism does not add to their antibiotic effects, but has led to extensive research on chemically modified tetracyclines or CMTs (likeincyclinide) for the treatment ofrosacea,acne,diabetesand various types ofneoplasms.[24][25][26] It has been shown that tetracyclines are not only active against broad spectrum of bacteria, but also against viruses, protozoa that lack mitochondria and some noninfectious conditions. The binding of tetracyclines to cellular dsRNA (double stranded RNA) may be an explanation for their wide range of effect. It can also be attributed to the nature of ribosomal protein synthesis pathways among bacteria.[23] Incyclinide was announced to be ineffective for rosacea in September 2007.[27] Several trials have examined modified and unmodified tetracyclines for the treatment of human cancers; of those, very promising results were achieved with CMT-3 for patients withKaposi Sarcoma.[28]

Structure-activity relationship

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Tetracyclines are composed of a rigid skeleton of 4 fused rings.[2]The rings structure of tetracyclines is divided into an upper modifiable region and a lower non modifiable region.[29][30]An active tetracycline requires a C10 phenol as well as a C11-C12 keto-enol substructure in conjugation with a 12a-OH group and a C1-C3 diketo substructure.[2][30][29]Removal of the dimethylamine group at C4 reduces antibacterial activity.[30][29]Replacement of the carboxylamine group at C2 results in reduced antibacterial activity but it is possible to add substituents to the amide nitrogen to get more soluble analogs like the prodruglymecycline.[2]The simplest tetracycline with measurable antibacterial activity is 6-deoxy-6-demethyltetracycline and its structure is often considered to be the minimum pharmacophore for the tetracycle class of antibiotics.[2][31]C5-C9 can be modified to make derivatives with varying antibacterial activity.[30][29]

Mechanism of resistance

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Cells can becomeresistantto tetracycline byenzymaticinactivation of tetracycline,efflux,ribosomal protection,[2]reduced permeability and ribosome mutation.[5]

Inactivation is the rarest type of resistance,[32]where NADPH-dependentoxidoreductase,a class of antibiotic destructase, modifies the tetracycline antibiotic at their oxidative soft spot leading to an inactivation of the tetracycline antibiotic. For example, the oxireductase makes a modification on the C11a site of oxytetracycline. Both Mg2+chelation and ribosome binding are required for thebiological activityof oxytetracycline and the modification attenuate the binding, leading to inactivation of the oxytetracycline antibiotic.[5]

In the most common mechanism of reaction, efflux,[23]various resistance genes encode a membrane protein that actively pumps tetracycline out of the cell by exchanging a proton for a tetracycline cation complex. This exchange leads to a reduced cytoplasmic concentration of tetracycline.[33]

In ribosomal protection, a resistance gene encodes a protein that can have several effects, depending on whatgeneis transferred.[34]Twelve classes of ribosomal protection genes/proteins have been found.[35]

Possible mechanisms of action of these protective proteins include:

  1. blocking tetracyclines from binding to the ribosome[36]
  2. binding to the ribosome and distorting the structure to still allow t-RNA binding while tetracycline is bound[37]
  3. binding to the ribosome and dislodging tetracycline[36][38]

Administration

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When ingested, it is usually recommended that the morewater-soluble,short-acting tetracyclines (plain tetracycline, chlortetracycline,oxytetracycline,demeclocyclineandmethacycline) be taken with a full glass of water, either two hours after eating or two hours before eating. This is partly because most tetracyclines bind with food and also easily withmagnesium,aluminium,ironandcalcium,which reduces their ability to be completelyabsorbedby the body. Dairy products,antacidsand preparations containing iron should be avoided near the time of taking the drug. Partial exceptions to these rules occur fordoxycyclineandminocycline,which may be taken with food (though not iron, antacids, or calcium supplements).Minocyclinecan be taken with dairy products because it does not chelate calcium as readily, although dairy products do decrease absorption of minocycline slightly.[39]

History

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The history of the tetracyclines involves the collective contributions of thousands of dedicated researchers, scientists, clinicians, and business executives. Tetracyclines were discovered in the 1940s, first reported in scientific literature in 1948, and exhibited activity against a wide range of microorganisms. The first members of the tetracycline group to be described were chlortetracycline and oxytetracycline.[2][40]Chlortetracycline(Aureomycin) was first discovered as an ordinary item in 1945 and initially endorsed in 1948[41]byBenjamin Minge Duggar,a 73-year-old emeritus professor of botany employed by American Cyanamid – Lederle Laboratories, under the leadership ofYellapragada Subbarow.Duggar derived the substance from a Missouri soil sample, golden-colored, fungus-like, soil-dwelling bacterium namedStreptomyces aureofaciens.[42] About the same time as Lederle discovered aureomycin,Pfizerwas scouring the globe for new antibiotics. Soil samples were collected from jungles, deserts, mountaintops, and oceans. But ultimatelyoxytetracycline(terramycin) was isolated in 1949 by Alexander Finlay from a soil sample collected on the grounds of a factory in Terre Haute, Indiana.[43]It came from a similar soil bacterium named Streptomyces rimosus.[44]From the beginning, terramycin was a molecule enveloped in controversy. It was the subject of the first mass-marketing campaign by a modern pharmaceutical company.Pfizeradvertised the drug heavily in medical journals, eventually spending twice as much on marketing as it did to discover and develop terramycin. Still, it turnedPfizer,then a small company, into a pharmaceutical giant.[43] ThePfizergroup, led by Francis A. Hochstein, in loose collaboration with and Robert Burns Woodward, determined the structure ofoxytetracycline,enabling Lloyd H. Conover to successfully producetetracyclineitself as a synthetic product.[45]In 1955, Conover discovered that hydrogenolysis of aureomycin gives a deschloro product that is just as active as the original product. This proved for the first time that chemically modified antibiotics could have biological activity. Within a few years, a number of semisynthetic tetracyclines had entered the market, and now most antibiotic discoveries are of novel active derivatives of older compounds.[43] Other tetracyclines were identified later, either as naturally occurring molecules, e.g., tetracycline from S. aureofaciens, S. rimosus, and S. viridofaciens and dimethyl-chlortetracycline from S. aureofaciens, or as products of semisynthetic approaches, e.g., methacycline, doxycycline, and minocycline.[2][41]

Research conducted byanthropologistGeorge J. Armelagosand his team atEmory Universityshowed that ancientNubiansfrom the post-Meroiticperiod (around AD 350) had deposits of tetracycline in their bones, detectable through analyses of cross-sections throughultravioletlight – the deposits are fluorescent, just as are modern ones. Armelagos suggested that this was due to ingestion of the localancient beer(very much like the Egyptian beer[46]), made from contaminated stored grains.[47]

Development

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Tetracyclines were noted for their broad spectrum antibacterial activity and were commercialized with clinical success beginning in the late 1940s to the early 1950s. The second-generation semisynthetic analogs and more recent third-generation compounds show the continued evolution of the tetracycline platform towards derivatives with increased potency as well as efficacy against tetracycline-resistant bacteria, with improved pharmacokinetic and chemical properties.[40] Shortly after the introduction of tetracycline therapy, the first tetracycline-resistant bacterial pathogen was identified. Since then, tetracycline-resistant bacterial pathogens have continued to be identified, limiting tetracycline's effectiveness in treatment of bacterial disease.[48]

Glycylcyclines and fluorocyclines are new classes of antibiotics derived from tetracycline.[49][50][48]These tetracycline analogues are specifically designed to overcome two common mechanisms of tetracycline resistance, namely resistance mediated by acquired efflux pumps and/or ribosomal protection. In 2005,tigecycline,the first member of a new subgroup of tetracyclines named glycylcyclines, was introduced to treat infections that are resistant to other antimicrobials.[51]Although it is structurally related tominocycline,alterations to the molecule resulted in its expanded spectrum of activity and decreased susceptibility to the development of resistance when compared with other tetracycline antibiotics. Likeminocycline,tigecyclinebinds to the bacterial 30S ribosome, blocking the entry of transfer RNA. This ultimately prevents protein synthesis and thus inhibiting bacterial growth. However, the addition of an N,N,-dimethylglycylamido group at the 9 position of the minocycline molecule increases the affinity oftigecyclinefor the ribosomal target up to 5 times when compared withminocyclineortetracycline.This allows for an expanded spectrum of activity and decreased susceptibility to the development of resistance.[48]Whiletigecyclinewas the first tetracycline approved in over 20 years, other, newer versions of tetracyclines are currently in human clinical trials.[52]

List of tetracycline antibiotics

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Antibiotic (INN) Source[40] Half-life[53] Notes
Tetracycline Naturally occurring 6–8 hours (short)
Chlortetracycline 6–8 hours (short)
Oxytetracycline 6–8 hours (short)
Demeclocycline 12 hours (intermediate)
Lymecycline Semi-synthetic 6–8 hours (short)
Meclocycline 6–8 hours (short) (no longer marketed)
Methacycline 12 hours (intermediate)
Minocycline 16+ hours (long)
Rolitetracycline 6–8 hours (short)
Doxycycline 16+ hours (long)
Tigecycline Glycylcyclines 16+ hours (long)
Eravacycline Newer 16+ hours (long) (formerly known as TP-434) received FDA approval on August 27, 2018, for treatment of complicated intra-abdominal infections.[54]
Sarecycline 16+ hours (long) (formerly known as WC 3035) received FDA approval on October 1, 2018, for treatment of moderate to severeacne vulgaris.[55]Sarecycline is anarrow-spectrumantibiotic.[56][57]
Omadacycline 16+ hours (long) (formerly known as PTK-0796[58]) receivedFDAapproval on October 2, 2018, for treatment ofcommunity-acquired pneumonia[59]and acuteskin and skin structure infections.[60]

Use as research reagents

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Members of the tetracycline class of antibiotics are often used as researchreagentsinin vitroandin vivobiomedical research experiments involving bacteria as well in experiments in eukaryotic cells and organisms with inducible protein expression systems usingtetracycline-controlled transcriptional activation.[61]The mechanism of action for the antibacterial effect of tetracyclines relies on disrupting protein translation in bacteria, thereby damaging the ability of microbes to grow and repair; however protein translation is also disrupted in eukaryoticmitochondrialeading to effects that mayconfoundexperimental results.[62][63] It can be used as an artificialbiomarkerin wildlife to check if wild animals are consuming a bait that contains avaccineor medication. Since it isfluorescentand binds tocalcium,a UV lamp can be used to check if it is in a tooth pulled from an animal. For example, it was used to check uptake of oralrabies vaccinebaits byraccoonsin the USA. However, this is an invasive procedure for the animal and labour-intensive for the researcher. Therefore, other dyes such asrhodamine Bthat can be detected in hair and whiskers are preferred.[64]

See also

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