Site author Richard Steane

The BioTopics website gives access to interactive resource material, developed to support the learning and teaching of Biology at a variety of levels.

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

Beta-lactams prevent bacteria from constructing a cell wall, by binding to PBP (Penicillin-binding proteins) which are enzymes inside bacterial cells involved in the final stages (cross-linking of the peptide subunits) in the synthesis of peptidoglycan, which is the major component of bacterial cell walls.
Contain a beta-lactam 'ring' which attaches to the active site of the bacterial enzymes.

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.

H2N is the amino group,
and the square section is the penam ring
Other 3D images are available

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

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.

Cephalosporins are based on a chemical substance produced by the mould Cephalosporium acremonium
β-Lactams containing 7-aminocephalosporanic acid nucleus and sidechain containing 3,6-dihydro-2H-1,3-thiazine rings
Most have "Ceph-" or "cef- " at the beginning of their name
Subdivided into (five) "generations" according to their target organism
Initially used against Gram-positive bacteria, but later versions increasingly used against a wider range of pathogens (and less effective against Gram-positives)
Less susceptible to penicillinases, but bacteria with extended-spectrum beta-lactamase (ESBL) have caused problems
Some have been developed with a variety of side-chains in order to avoid breakdown by bacterial beta lactamase enzymes produced by penicillin-resistant bacterial strains, or to attach to different PBPs, to pass the blood brain barrier, and ionise to facilitate entry into Gram-negative bacterial cells.

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. The basic carbenapem structure

Carbapenems are based on a chemical substance produced by the actinomycete Streptomyces cattleya
Similar in structure to the penicillins, but with a carbon atom in position 1 instead of sulphur (hence the name)
Most have "-penem" on the end of their name
Broadest antibacterial spectrum of beta-lactams - active against both Gram-positive and Gram-negative bacteria, and anaerobes
One of the antibiotics of last resort for many bacterial infections, and mainstay of therapy in patients with serious hospital-acquired infection
Must be injected
Carbapenem antibiotic resistance is a recent scare story originating from Asia
Carbapenem resistance due to genes on plasmids can be passed amongst different species

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. macrolide ring structure - lactone on the left, desosamine top right, cladinose bottom right

macrolide ring structure - lactone on the left, desosamine top right, cladinose bottom right

Macrolides act as bacterial protein synthesis inhibitors
Bind to the bacterial ribosome, preventing addition of amino acids to polypeptide chains
Based on a chemical substance produced by the actinomycete Saccharopolyspora erythraea
14-, 15-, or 16-membered macrocyclic lactone rings with unusual deoxy sugars L-cladinose and D-desosamine attached
Difficult to synthesise chemically
Most have "-omycin" on the end of their name
Different compounds produced by substitution of side groups onto erythromycin
Antimicrobial spectrum slightly wider than that of penicillins
May be used for people who have an allergy to penicillins
Used at lower doses, may reduce inflammation by adjusting the immune response
May build up in the body due to liver recycling it into bile
Streptococcus pneumoniae and other species have developed resistance to macrolides.

Examples:

Erythromycin
Azithromycin

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. Basic 4-chain structure of Tetracyclines

Tetracyclines act as bacterial protein synthesis inhibitors
Bind to the bacterial ribosome, preventing addition of amino acids to polypeptide chains
Based on chemical substances produced by various Streptomyces species
4 hydrocarbon rings
Most have "-cycline" on the end of their name
Some naturally produced, some semi-synthetic - produced by substitution of side groups
Side effects sometimes cause problems
May be used in the control of other non-microbial parasites in malaria and elephantiasis
Food reduces the absorption of tetracycline, so it should be taken at least two hours before or after meals
Originally quite a wide antimicrobial spectrum but resistance is now a problem

Examples:

lymecycline

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. Nalidixic acid - technically, it is a naphthyridone, not a quinolone: its ring structure is a 1,8-naphthyridine nucleus that contains two nitrogen atoms, not quinoline, which has a single nitrogen atom.

Nalidixic acid - technically, it is a naphthyridone, not a quinolone: its ring structure is a 1,8-naphthyridine nucleus that contains two nitrogen atoms, not quinoline, which has a single nitrogen atom.

Quinolones interfere with DNA replication and transcription in bacteria
Synthetic chemotherapeutic antibacterial compounds containing the quinolone nucleus or the naphthyridone nucleus, both ring structures
Many have "-oxacin" on the end of their name (fluoroquinolones: "-floxacin")
All synthetic
Development has produced four generations, with extra ring structures and substituents, extending their antimicrobial spectrum, particularly versus anaerobic bacteria
Side effects e.g. toxicity sometimes cause problems
Numerous pathogens now exhibit resistance worldwide.

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". Streptomycin molecule

Aminoglycosides act as bacterial protein synthesis inhibitors
Compounds of (usually 3) amino-sugars connected by glycosidic bonds
Some derived from bacteria of the Streptomyces genus (with the suffix -mycin) or Micromonospora, ( suffix -micin).
Side effects e.g. ototoxicity sometimes cause problems

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.

The sulphonamide group acts as an analogue of PABA (para-amino benzoic acid) which is involved in folate synthesis, thus starving the bacteria of the B-group vitamin folate.
Sulfanilamide (an intermediate in the dye-making industry) has several clinical disadvantages which can be reduced by adding different sidechains.
Possible side effects include hypersensitivity (allergic reactions), liver and kidney damage.

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. Vancomycin - listing monomers
Thanks to Norine - see reference below

Vancomycin - listing monomers
Thanks to Norine - see reference below

glycopeptides are produced in fermentation by various micro-organisms
prevent bacterial cell wall synthesis (different mechanism to penicillin)
structure: glycosylated .. cyclic or polycyclic .. nonribosomal peptides
most include amino acids differing from the normal 20 in proteins, perhaps connected by bonds other than peptide or disulfide bonds
used against Gram-positive microorganisms
toxicity of early isolates ("Mississippi mud" - contained impurities) slowed down early development
the related compound avoparcin (animal "growth promoter" produced by Cyanamid) has stimulated development of resistance (not in USA, banned in Europe in 1997, recently dropped in Australia)
Vancomycin-resistant enterococci (VRE) emerged in the mid-1980s
Vancomycin-resistant Staphylococci emerged in the mid-1990s
Vancomycin and related compounds were considered as drugs of last resort for treating MRSA

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. 1,3 oxazolidine-2-one
- needs aromatic substituent at 3 and sidechain at 5

entirely synthetic
based on the 5-membered oxazolidinone ring containing both nitrogen and oxygen
act as protein synthesis inhibitors

Linezolid is one such compound that came to prominence in 1996 and was approved by the FDA in 2000, but most patents expired in 2015.
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 molecular 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:

It has a 13-member amino acid chain, 10 of which form into a loop
Several of these are unusual - non proteinogenic; others are D-forms (rather than the normal L-forms which are usually found in proteins)
Some amino acids are hydrophobic (lipophilic) and act together with a decanoyl (10 carbon) hydrocarbon side-chain
The lipophilic daptomycin tail inserts itself into the bacterial cell membrane, and alters its shape/curvature
This causes rapid membrane depolarization and loss of potassium ions

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)

Chemical_Structure_of_Teixobactin_based_on_Nature_Article.svg (34K)

is a depsipeptide - a molecule that has both peptide and ester linkages in proximity in the same amino acid chain
is produced in 'normal' fermentation process following acclimatisation to standard microbiological techniques
prevents bacterial cell wall synthesis - by targeting bacterial lipids, not proteins
consists of a peptide chain of 11 amino acids, with a square loop at the end
has 2 out of 11 amino acids different from the normal 20 in proteins, and loop formed by ester bond
shows considerable promise against Gram-positive microorganisms and also TB
is active against MRSA and other bacterial strains resistant to other antibiotics
is unlikely to become useless as quickly as other antibiotics due to the development of bacterial resistance to it

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)

is a cyclic peptide - a ring-shaped molecule composed of amino acids linked by peptide bonds
consists of a loop of 6 amino acids, one incorporating a thiazolidine group
is built from mostly fairly normal amino acids, but several are D-forms (rather than the normal L-forms which are usually found in proteins)
is active against Staphylococcus aureus - a common commensal species in the nasal cavity, also MRSA and other bacterial strains resistant to other antibiotics

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

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

Antibiotic prescribing Nuffield trust looks at prescribing patterns for antibiotics, both in England and internationally.

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

Linezolid from National Institute for Health and Care Excellence (NICE)

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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Types of antibiotics

Beta-lactams

Penicillins (penams)

Cephalosporins (cephems)

First generation

Second generation

Second generation cephamycins

Third generation

Fourth generation

Fifth generation

Monobactams

Carbapenems

Macrolides

Tetracyclines

Quinolones

Aminoglycosides

Sulphonamides/sulfonamides (sulpha/sulfa drugs) and Trimethoprim

Glycopeptides

Oxazolidinones

Lipopeptides

Depsipeptide

Cyclic peptide

Web references

Sulphonamides/sulfonamides (sulpha/sulfa drugs)
and Trimethoprim