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Types of antibiotics

Like other drugs, antibiotics are marketed under a variety of names. Here I have restricted myself to using the standard generic name of each antibiotic. For each category, I have given a brief historical introduction, naming key people where possible. I have also given some chemical information on their molecular structure and mode of action, backed up in some cases with links to interactive 3D molecule displays (using the Javascript Jsmol format) on this website. Other information should be visible as you pass the mouse cursor over green body text.

Click below to jump to the following categories of antibiotics:
Beta-lactams, Macrolides, Tetracyclines, Quinolones, Aminoglycosides, Sulfonamides, Glycopeptides, Oxazolidinones, Lipopeptides, Depsipeptide, Cyclic peptide

Beta-lactams

Sub-categories: penicillins (penams), cephalosporins (cephems), monobactams, carbapenems

Penicillins (penams)

It is known that Alexander Fleming discovered penicillin by chance in 1928 when a mould grew on bacterial culture plates which he had not cleared away. He named the substance penicillin after identifying the mould as a Penicillium, and showed its effect on a variety of bacteria, but he could not develop the techniques necessary to culture the mould and extract the penicillin. With the stimulus of the second world war, Ernst Chain and Edward Abraham, together with Norman Heatley, working under Howard Florey, took up the challenge and worked out how to grow the mould and concentrate penicillin. In 1945 Fleming, Chain and Florey were awarded the Nobel Prize for medicine. Fleming was elected FRS in 1943 and knighted in 1944.

Interestingly, in 1921 Fleming had discovered the antibacterial enzyme lysozyme which is in egg white, tears and some other body secretions when he added nasal mucus to a bacterial culture plate.
  • Penicillins are based on a chemical substance produced by the mould Penicillium notatum
  • They are β-Lactams containing a nucleus of 6-aminopenicillanic acid (lactam plus thiazolidine ring) and other ring side-chains
  • Most have "-cillin" on the end of their name
  • Subdivided into spectra according to their target organism
  • Mostly used against Gram-positive bacteria, but attempts have been made to extend their effectiveness
  • Some have been developed semi-synthetically with different side-chains to give different properties: oral administration rather than by injection, or to avoid breakdown by bacterial penicillinase (beta lactamase) enzymes produced by penicillin-resistant bacterial strains
  • Side-chains may contribute to side effects e.g. allergic reaction
  • Some have been used in combination with a non-antibiotic compound with a similar structure to penicillin, that acts as an inhibitor of bacterial penicillinase
  • However MRSA has developed resistance to methicillin, flucloxacillin and other penicillins by also having an altered penicillin-binding protein.

6-aminopenicillanic acid
Spectrum Narrow Moderate
(amino-penicillins)
Broad
(combination antibiotic)
Extended
(ureidopenicillins and carboxypenicillins)
Active against Staphylococci and Streptococci Staphylococci (sensitive strains only), Haemophilus influenzae, Salmonella, Listeria, and Group A streptococci bacteria to left, and possibly Klebsiella bacteria to left, and possibly Pseudomonas spp (Gram negative)
Examples
ß-lactamase sensitive
Benzylpenicillin (penicillin G), Phenoxymethylpenicillin (penicillin V)
ß-lactamase resistant
Methicillin, Cloxacillin, Flucloxacillin, Dicloxacillin
amoxicillin, ampicillin co-amoxiclav (amoxicillin plus clavulanic acid, a non-antibiotic compound with a similar structure to penicillin that acts as an inhibitor of penicillinase produced by penicillin-resistant bacterial strands) azlocillin, mezlocillin , piperacillin, carbenicillin* , ticarcillin*
* likely to be used in conjunction with a penicillinase inhibitor


In the NHS, Penicillins are the most commonly prescribed antibiotics (in the year to September 2009, 18.9 million items, costing £49 million).
Four antibiotics accounted for 99% of use of penams:
Penam Antibiotic Number of items
(million prescriptions)
% of items used % of cost Actual cost
(£ million)
amoxicillin 10.7 56 32 15.7
flucloxacillin 3.7 20 31 15.2
phenoxymethylpenicillin 2.4 13 11 5.5
co-amoxiclav 1.9 10 19 9.5
others
by difference
0.2 1 7 3.1

Cephalosporins (cephems)

In 1945, Giuseppe Brotzu isolated a fungus Cephalosporium acremonium from seawater near a sewage outflow in Cagliari, Sardinia, and showed that it killed Salmonella typhi. Unable to develop it further, he passed the fungal culture to the Oxford group resposible for penicillin. Edward Abraham extracted several cephalosporins, and used money from patenting them for several charitable purposes. Abraham was elected FRS in 1958, awarded CBE in 1973 and knighted in 1980. In the NHS, Cephalosporins prescribing and spending has decreased by 21% and 35% over the last five years. (See commonly prescribed antibiotics.)
In the year to September 2009, 2.5 million items were prescribed, costing £8.8 million).
Two antibiotics accounted for 84% of the use of cephalosporins:
Cephalosporin Antibiotic Number of items
(million prescriptions)
Actual cost
(£ million)
Cefalexin 1.9 4.4
Cefaclor 0.2 1.8

First generation

Moderate spectrum - "PEcK"
against Proteus mirabilis, Esherichia coli, Klebsiella pneumoniae Not MRSA
e.g. cephalexin

Second generation

Moderate spectrum with anti-Haemophilus activity - "HEN"
against Haemophilus influenza, Enterobacter aerogenes, Neisseria
e.g.cefaclor

Second generation cephamycins

Moderate spectrum with anti-anaerobic activity
e.g. cefotetan

Third generation

Broad spectrum
e.g. ceftriaxone

Broad spectrum with anti-Pseudomonas activity
e.g. ceftazidime

Fourth generation

Broad spectrum with enhanced activity against Gram positive bacteria and ß-lactamase stability
e.g. cefepime

Fifth generation

Antipseudomonal and less susceptible to development of resistance
e.g. Ceftobiprole

Monobactams

Discovered in 1979 as a result of "a novel screening procedure", this class of antibiotics were named (monocyclic bacterially produced beta - lactams) and developed by Sykes et al, workers at the Squibb Institute for Medical Research New Jersey.
  • Monobactams are based on a chemical substance produced by the bacterium Chromobacterium violaceum.
  • Contain beta-lactam ring alone, not fused to another ring: based on 3-AMA (3 aminomonobactamic acid) - chemically similar to 6-APA
  • Strong activity against susceptible gram-negative bacteria, including Pseudomonas aeruginosa
  • Effective against a wide range of bacteria including Citrobacter, Enterobacter, E. coli, Haemophilus, Klebsiella, Proteus, and Serratia species
  • No useful activity against gram-positive bacteria or anaerobes
  • Must be injected or inhaled


3-aminomonobactamic acid
Only real example: aztreonam.

Carbapenems

This is a group of about 6 antibiotics released from 1985 and seen as our last effective defence against multi-resistant bacterial infections, but carbapenem resistance itself is now a cause for concern. Examples:
Meropenem
Imipenem + Cilastin (to prevent kidney damage)

Macrolides

In 1952 erythromycin was isolated by Eli Lilly's research team, led by J. M. McGuire, from the metabolic products of a strain of fungus Saccharopolyspora erythraea found in Filipino soil samples. Examples:
Erythromycin
Azithromycin

In the NHS, Macrolides are the second most commonly prescribed antibiotics (in the year to September 2009, 4.2 million items, costing £26.7 million).
Three antibiotics accounted for 100% of use of macrolides:
Macrolide Antibiotic Number of items
(million prescriptions)
Actual cost
(£ million)
Erythromycin 2.8 12.5
clarithromycin 1.2 8.1
azithromycin 0.2 6.1

Tetracyclines

In 1945, at the age of 73, Benjamin Duggar discovered chlortetracycline (Aureomycin), the first of the tetracycline antibiotics, from a soil bacterium growing in allotment soil. Several major drug companies tried to develop and patent similar compounds but accommodated one another with cross-licencing. In late 1958, the U.S. government charged Pfizer and American Cyanamid with price fixing in connection with tetracycline and witholding information, but lost the final appeal in 1982. Examples:
lymecycline

In the NHS, prescribing and spending of Tetracyclines have increased by 20%, but costs have decreased by 20% in a year. (See commonly prescribed antibiotics.)
In the year to September 2009, 3.1 million items were prescribed, costing £20.6 million.
Four antibiotics accounted for 98% of the use of tetracyclines:
Tetracycline Antibiotic Number of items
(million prescriptions)
Actual cost
(£ million)
doxycycline 1.3 2.7
oxytetracycline 0.858 3.2
lymecycline 0.645 8.3
minocycline 0.234 4.4
others
by difference
0.063 2

Quinolones

Nalidixic acid was discovered in the early 1960s during research of antimalarial agents - it was a by-product of the synthesis of chloroquine.

Since then, more than 10,000 analogues and derivative compounds have been developed and more than 800 million patients have been treated with quinolones. Examples:
Ciprofloxacin, Levofloxacin

Aminoglycosides

Selman A. Waksman, professor of biochemistry and microbiology at Rutgers University New Jersey USA, was interested in screening soil micro-organisms and led a team that discovered over twenty antibiotics, as well as coining the term antibiotic! He was credited with the discovery of streptomycin, which was greatly used against Mycobacterium tuberculosis.

In fact he had little to do with it; it was Albert Schatz, then a 23-year old graduate student in his laboratory, returning from war duty and inspired to find an antibiotic to treat tuberculosis, who first isolated streptomycin in 1943, essentially working in isolation. After the major commercial success of streptomycin, Schatz had to sue Waksman in order to be (at least partially) credited with the discovery. In 1994, Schatz was awarded the Rutgers medal for his work on developing streptomycin.

From patent income, Waksman established a foundation for microbiological research, which established the Waksman Institute of Microbiology located at Rutgers University. He was awarded the 1952 Nobel Prize in Physiology or Medicine "for the discovery of streptomycin". Examples:
Streptomycin
Neomycin

Sulphonamides/sulfonamides (sulpha/sulfa drugs)
and Trimethoprim

Although these are antibacterial or antimicrobial, they are often described as chemotherapeutic rather than antibiotic because they are synthesised chemically. Some sulphonamides are not antibacterial and have other medical functions e.g. diuretics, anti-glaucoma agents, anticonvulsants.

In 1932 the first antibacterial sulphonamide drug, a red azo-dye called Prontosil, was found to be active against bacterial infections in mice, but it did not show antibacterial activity on its own in the laboratory. It was later found that it was converted into sulfanilamide (bioactivated) which was active and Prontosil was described as a prodrug. Examples: Sulfamethoxazole

In contrast to the chance discovery of sulpha drugs, a compound with a similar mode of action, Trimethoprim, was developed by Gertrude Belle Elion and George H. Hitchings. In a long career involving nucleic acid metabolism, Elion and Hitchings introduced chemical treatments for several diseases. They concentrated on biochemical differences between normal and diseased human body cells and pathogenic bacteria and viruses and investigated compounds that block metabolic pathways.

Together with Sir James W. Black, Elion and Hitchings gained the Nobel Prize in Physiology or Medicine.

Trimethoprim

Glycopeptides

In 1956 Dr. E. C. Kornfeld, organic chemist at Eli Lilly, isolated vancomycin (as compound 05865) from a soil sample containing Streptomyces orientalis from the Borneo jungle. Examples: vancomycin, teicoplanin, telavancin, bleomycin, ramoplanin, and decaplanin

Oxazolidinones

Oxazolidinones are heterocyclic organic compounds, some of which were found to have antibiotic properties in the mid 1980s. Since resistance to other types of antibiotics had become a problem, these compounds were given special attention. Linezolid is one such compound that came to prominence in 1996 and was approved by the FDA in 2000. It is not cheap: cost to the UK NHS is £670-£890 per treatment - $1000-2000 in the US.
Other oxazolidinone antibiotics are currently being developed.

It is interesting that most of the recent discoveries in the field of antibiotics have been peptides with a looped mole cular structure.

Lipopeptides

In the late 1980s, researchers at Eli Lilly and Company investigated the compound LY 146032 - later named Daptomycin - produced by the soil saprotroph Streptomyces roseosporus.

However it was not further developed until Cubist Pharmaceuticals acquired the rights to it in 1995 and under the name Cubicin it was approved by the US FDA in 2003 for use against complicated skin and skin structure infections (cSSSI).
Daptomycin (24K)
Daptomycin is a lipopeptide:

Example: Daptomycin
Other lipopeptides also have antibiotic or antifungal properties.


Depsipeptide

In January 2015 Dr. Kim Lewis, director of Northeastern University's Antimicrobial Discovery Center, announced the discovery of teixobactin, a new antibiotic that bacteria will possibly not become resistant to for decades. It was produced by a new organism, within the class β-proteobacteria, Eleftheria terrae, isolated from soil from Maine, USA following the adoption of a novel technique.
This development involved a large team of specialist workers at different sites in the USA, Germany and UK.
The isolation technique involved iChips - isolation chips - multiple small diffusion chambers buried in soil for weeks, so as to absorb environmental growth factors.
Colonising microorganisms eventually adapted for growth under otherwise prohibitive in vitro conditions in the lab.
Several thousand isolates were screened for antibiotic production: teixobactin emerged as the most promising out of 25 'possibles', patented by NovoBiotic Pharmaceuticals, Cambridge, Massachusetts, USA.
Chemical_Structure_of_Teixobactin_based_on_Nature_Article.svg (34K) Example: teixobactin

More on this website about the isolation technique

Cyclic peptide

In July 2016 Andreas Peschel and Bernhard Krismer announced a 'novel' antibiotic which they called lugdunin.
It was produced by a commensal organism, Staphylococcus lugdunensis, isolated from the human nasal cavity. This organism was first described in 1988 but it has occasionally been implicated in causing some infections.
The discovery of the compound and the elucidation of its structure involved a team of specialist workers at the University of Tübingen, Germany.
This followed the observation that human nasal colonisation by S. lugdunensis was associated with a significantly reduced S. aureus carriage rate
They conclude that human microbiota should be considered as a source for new antibiotics. lugdunin (26K) Example: Lugdunin


Web references

Antibiotic ApocalypseBBC Panorama TV programme

Antibiotics timeline From Wikipedia, the free encyclopedia

Penicillin From Wikipedia, the free encyclopedia

Amoxicillin From Wikipedia, the free encyclopedia

The True Story of the Discovery of Streptomycin by Albert Schatz {NO LONGER AVAILBLE?} But see below

Notebooks Shed Light on an Antibiotic’s Contested Discovery By PETER PRINGLE

NHS Antibiotic prescribing information commonly prescribed antibiotics

The fluoroquinolones: structures, mechanisms of action and resistance, and spectra of activity in vitro. J S Wolfson and D C Hooper

Activities of Quinolones Against Obligately Anaerobic Bacteria - Figure 3 shows the development of the quinolones and naphthyridones since the early 1960s as an "evolutionary" tree

The Nobel Prize in Physiology or Medicine 1988 Sir James W. Black, Gertrude B. Elion, George H. Hitchings

Norine (database of nonribosomal peptides)

A new antibiotic kills pathogens without detectable resistance - a 21-author paper on Teixobactin in Nature

Daptomycin From Wikipedia, the free encyclopedia

Daptomycin: a lipopeptide antibiotic for the treatment of serious Gram-positive infections

In vitro and in vivo activity of LY 146032, a new cyclic lipopeptide antibiotic.

Daptomycin biosynthesis in Streptomyces roseosporus: cloning and analysis of the gene cluster and revision of peptide stereochemistry

Human commensals producing a novel antibiotic impair pathogen colonization 17-author paper on Lugdunin in Nature

Staphylococcus lugdunensis: the coagulase-negative staphylococcus you don't want to ignore

Too much of a good thing The Daily Telegraph

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